1. Clinical Approach to Blood Disorders

A systematic clinical approach to hematologic disease begins with the peripheral blood smear (PBS), the complete blood count (CBC), and targeted ancillary testing. This section provides the diagnostic framework used in hematology subspecialty practice and on the internal medicine board examination.

1.1 CBC Interpretation — Systematic Approach

The CBC provides a quantitative snapshot of all three cell lines. Abnormalities should prompt peripheral smear review before ordering further tests.

Parameter	Reference Range (Adult)	Low → Differential	High → Differential
Hemoglobin (g/dL)	M: 13.5–17.5 / F: 12–16	Anemia: classify by MCV, retic count	Polycythemia: PV vs secondary
MCV (fL)	80–100	<80: microcytic (IDA, thal, ACD); >100: macrocytic (B12/folate, MDS, liver Dx)	See macrocytic workup
Reticulocyte count (%)	0.5–2.0%	Hypoproliferative (aplasia, PRCA, BMF)	Hemolysis, hemorrhage, recovery
WBC (×10³/µL)	4–11	Neutropenia (<1.5 ANC), pancytopenia	Leukocytosis, leukemia, reactive
Platelets (×10³/µL)	150–400	<150: thrombocytopenia (ITP, TTP, HIT, BM failure)	>450: reactive vs ET
RDW (%)	11.5–14.5	Narrow = uniform cells (thalassemia trait)	Elevated = mixed population (IDA, folate def, mixed deficiency)

🔑 Board Pearl: In IDA, RDW is elevated early (anisocytosis) while MCV decreases later. In thalassemia trait, RDW is often normal despite microcytosis — the Mentzer Index (MCV/RBC): <13 suggests thalassemia; >13 suggests IDA.

1.2 Peripheral Blood Smear (PBS) — Spot Diagnosis

PBS review is essential for any CBC abnormality. Always examine the feather edge, body, and thick zone of the smear.

Morphology	Appearance	Clinical Association
Hypochromic microcytes	Small pale RBCs with enlarged central pallor (>1/3 diameter)	IDA, thalassemia, sideroblastic anemia, ACD severe
Macrocytes (oval)	Large oval cells without pallor	Megaloblastic anemia (B12/folate deficiency); MDS
Hypersegmented neutrophils	≥5 lobes (≥5%), or any cell with ≥6 lobes	Megaloblastic anemia — highly specific
Spherocytes	Round, dense, no central pallor	Hereditary spherocytosis, AIHA (warm)
Target cells (codocytes)	Central dense area + peripheral ring	Thalassemia, liver disease, IDA, HbC disease
Schistocytes / helmet cells	Fragmented RBCs	MAHA: TTP, HUS, DIC, mechanical heart valve, malignant HTN
Tear-drop cells (dacrocytes)	Pear-shaped, one pointed end	Primary myelofibrosis, thalassemia, bone marrow infiltration
Sickle cells (drepanocytes)	Elongated curved cells	Sickle cell disease (HbSS)
Bite cells (keratocytes)	Semicircular "bite" from one side	G6PD deficiency (after oxidative stress)
Blister cells (eccentrocytes)	Hemoglobin displaced to one side	G6PD deficiency, oxidative hemolysis
Rouleaux	RBCs stacked like coins	Multiple myeloma, macroglobulinemia (increased proteins)
Howell-Jolly bodies	Small nuclear remnant (dark dot)	Post-splenectomy, functional asplenia (SCD)
Basophilic stippling	Fine blue dots in cytoplasm	Lead poisoning, thalassemia, sideroblastic anemia
Auer rods	Pink/red needle-shaped crystals in blast cytoplasm	AML (pathognomonic — especially APL M3)
Leukoerythroblastic picture	Immature WBCs (metamyelocytes) + nucleated RBCs	Bone marrow infiltration (metastatic cancer, myelofibrosis, leukemia)
Pseudo-Pelger-Huet	Bilobed "pince-nez" neutrophils	MDS (acquired), drugs (mycophenolate, colchicine)

🎯 High-Yield: PBS Findings That Require Urgent Action

Schistocytes + thrombocytopenia + elevated LDH → TTP/HUS — urgent plasma exchange or eculizumab (do NOT transfuse platelets)
Auer rods in blast → APL — start ATRA immediately before confirming molecular diagnosis (avoid delay)
Blasts >20% on smear → Acute leukemia — urgent hematology consultation
Leukoerythroblastic smear + splenomegaly → Primary myelofibrosis vs bone marrow infiltration

1.3 Bone Marrow Examination

Bone marrow aspirate and biopsy (BMAB) is indicated when PBS + CBC cannot explain the clinical picture. Posterior iliac crest is the standard site.

Indication	Aspirate vs Biopsy	Key Findings Expected
Pancytopenia workup	Both required	Aplasia (empty marrow), MDS dysplasia, infiltration, or leukemia
Suspected leukemia / MDS	Both + cytogenetics + flow cytometry	Blast percentage, dysplasia, cytogenetic aberrations
Staging lymphoma	Biopsy (trephine) preferred	Lymphomatous infiltration pattern (paratrabecular = follicular NHL)
Myeloma workup	Aspirate + biopsy + FISH	Plasma cell percentage, sheet-like infiltration
Unexplained splenomegaly	Aspirate + culture	Leishmaniasis (LD bodies), TB, storage disorders (Gaucher)
Myelofibrosis	Biopsy (dry tap from aspirate)	Reticulin/collagen fibrosis, megakaryocyte atypia

🔑 Normal BM Cellularity: Approximately 100 minus the patient's age (e.g., 40-year-old: ~60% cellularity normal). Cellularity <25% = aplastic anemia. M:E ratio normal = 3:1 (3 myeloid : 1 erythroid).

1.4 Coagulation Studies

Test	Pathway	Prolonged When	Key Conditions
PT/INR	Extrinsic (VII) + Common (X, V, II, I)	Factor VII deficiency, warfarin, liver disease, vitamin K deficiency, DIC	PT prolonged alone → early warfarin, factor VII def, early liver Dx
aPTT	Intrinsic (XII, XI, IX, VIII) + Common	Heparin, hemophilia A/B, vWD, lupus anticoagulant, factor XII deficiency	aPTT alone → hemophilia A (VIII), B (IX), XI; LA (no bleeding)
TT (Thrombin time)	Fibrinogen → Fibrin conversion	Heparin, hypofibrinogenemia, dysfibrinogenemia, dabigatran	TT most sensitive for heparin contamination
Fibrinogen	Direct substrate	DIC (consumed), liver disease, massive hemorrhage	Low in DIC; normal/elevated in early DIC or inflammatory states
D-dimer	Fibrin degradation product	DIC, VTE, malignancy, post-op, sepsis	Very sensitive for DIC; low specificity
Mixing study (1:1 with normal plasma)	Distinguish deficiency vs inhibitor	Corrects → factor deficiency; doesn't correct → inhibitor (LA, acquired hemophilia)	Incubated mixing study: 2h at 37°C for time-dependent inhibitors

🔑 Mixing Study Interpretation: If aPTT corrects with 1:1 mixing → factor deficiency (hemophilia A, B, XI). If does NOT correct → inhibitor present. Lupus anticoagulant inhibits immediately; acquired hemophilia A (anti-FVIII) inhibits after 2-hour incubation (time-dependent).

1.5 Hemoglobin Typing & Electrophoresis

Hemoglobin (Hb) electrophoresis / HPLC differentiates hemoglobin variants. Normal adult: HbA >95%, HbA2 2–3.5%, HbF <1%.

Hb Pattern	HbA	HbA2	HbF	HbS / HbE / HbH	Diagnosis
Normal adult	>95%	2–3.5%	<1%	0	Normal
Beta-thal trait	~90–94%	>3.5% (elevated)	<4%	0	Beta-thalassemia minor
Beta-thal major	0–30%	>3.5%	70–90%	0	Beta-thalassemia major (transfusion dependent)
HbE trait	~70%	Normal/slight ↑	Normal	HbE ~30%	HbE trait (Southeast Asian)
HbE/beta-thal	0–30%	↑	↑↑	HbE ~50–80%	HbE/beta-thal (most common severe thal in Thailand)
HbH disease	Reduced	Reduced	Variable	HbH ~5–30%	Alpha-thal 3-gene deletion (--/-α)
HbSS	0	Normal	5–20%	HbS ~80–95%	Sickle cell disease
HbAS	~60%	Normal	Normal	HbS ~40%	Sickle cell trait (benign carrier)

🔑 Thailand Context: HbE is extremely common in Southeast Asia (carrier rate ~30% in some regions). HbE alone = mild disease (not clinically significant). HbE/β-thal = most common cause of severe thalassemia in Thailand, requiring transfusion support.

📚 Key References

WHO 2021 — Global epidemiology of hemoglobin disorders
ASH 2020 — Practical guide to CBC interpretation
Dr. Pisa Phiphitaporn (KKU, 2026) — Spot diagnosis and counseling in hematology

2. Approach to Anemia

Anemia (Hb <13.5 g/dL men, <12 g/dL women) affects 25% of the global population. Systematic classification by MCV and reticulocyte count leads to efficient diagnosis.

2.1 Classification Algorithm

MCV	Retic Count	Category	Key Diagnoses
Low (<80 fL)	Low/normal	Microcytic hypoproliferative	IDA (most common worldwide), thalassemia, ACD, sideroblastic anemia
Normal (80–100 fL)	Low/normal	Normocytic hypoproliferative	ACD, early IDA, renal disease, aplastic anemia, hypothyroidism, PRCA
Normal (80–100 fL)	High (>2.5%)	Normocytic hyperproliferative	Hemolysis, acute hemorrhage (early), post-treatment recovery
High (>100 fL)	Low/normal	Macrocytic hypoproliferative	B12/folate deficiency, liver disease, hypothyroidism, MDS, drugs (MTX, hydroxyurea)
High (>100 fL)	High	Macrocytic hyperproliferative	Reticulocytosis (retics are large), hemolysis with B12 deficiency

🔑 Two-Step Approach: Step 1 — MCV (micro/normo/macro). Step 2 — Reticulocyte production index (RPI = retic% × Hct/0.45). RPI >2 = adequate marrow response (hemolysis/bleeding). RPI <2 = hypoproliferative (BM failure, deficiency, ACD).

2.2 Iron Deficiency Anemia (IDA)

IDA is the most common cause of anemia worldwide. Caused by decreased intake, malabsorption (celiac disease, H. pylori), increased demand (pregnancy), or chronic blood loss (GI, menorrhagia).

Iron Studies

Parameter	IDA	ACD	Thalassemia Trait	Sideroblastic
Serum Iron	↓↓	↓	Normal	↑
TIBC	↑↑	↓ or normal	Normal	Normal/↑
Transferrin Saturation	<10%	10–20%	Normal	>50% (sideroblastic)
Serum Ferritin	↓↓ (<12 ng/mL)	Normal/↑ (acute phase)	Normal	↑
MCV	↓	Normal/↓	↓↓	↓ or bimodal
RDW	↑ (anisocytosis)	Normal	Normal	↑ (bimodal)

🔑 Ferritin caveat: Ferritin is an acute phase reactant. In IDA with concurrent infection/inflammation/liver disease, ferritin may be falsely normal or elevated. Use ferritin <30 ng/mL as the threshold in inflammatory states. Soluble transferrin receptor (sTfR) is elevated in IDA but NOT in ACD — useful in combined states.

Clinical Features (Spot Diagnosis)

Sign/Symptom	Mechanism	Boards Relevance
Koilonychia (spoon nails)	Brittle nails from tissue iron depletion	Classic IDA sign — photographic question
Angular cheilitis / glossitis	Epithelial iron depletion	Smooth, beefy red tongue in IDA and B12/folate deficiency
Pica	Unknown — pagophagia (ice), geophagia (dirt)	Pathognomonic for IDA when present
Plummer-Vinson syndrome	IDA + postcricoid web + dysphagia	Pre-malignant lesion — risk of esophageal SCC; treat IDA ± dilation
Restless legs syndrome	Brain iron depletion affects dopaminergic pathways	IDA can cause/worsen RLS — check ferritin

Treatment

Oral ferrous sulfate 325 mg (65 mg elemental Fe) TID on empty stomach — expect Hb rise 1–2 g/dL per 3–4 weeks; treat 3–6 months after Hb normalization to replete stores
Vitamin C 500 mg with iron enhances absorption (reduces Fe³⁺ → Fe²⁺)
IV iron (ferric carboxymaltose, iron sucrose, low-molecular-weight dextran) — indicated for: malabsorption, intolerance to oral iron, severe anemia needing rapid repletion, inflammatory bowel disease, CKD
Always identify and treat the underlying cause (GI endoscopy if male or post-menopausal female)

2.3 Anemia of Chronic Disease (ACD)

ACD (also called anemia of inflammation) is the most common anemia in hospitalized patients. Caused by hepcidin upregulation in response to IL-6 from chronic infection, inflammation, or malignancy. Hepcidin blocks ferroportin → iron sequestration in macrophages → reduced iron delivery to erythroid precursors.

Feature	Detail
Typical Hb	Usually 8–11 g/dL (rarely severe)
MCV	Normocytic (70%), microcytic (30%) in long-standing disease
Key lab	↓ serum iron, ↓ TIBC, ↑ ferritin, ↑ hepcidin
PBS	Normochromic normocytic; sometimes mild hypochromia
Treatment	Treat underlying disease; ESA (epoetin alfa) for CKD/chemotherapy-associated; IV iron if ferritin <100 or TSAT <20%

2.4 Megaloblastic Anemia (B12 / Folate Deficiency)

Megaloblastic anemia results from impaired DNA synthesis in rapidly dividing erythroid precursors, causing nuclear-cytoplasmic asynchrony. Both B12 and folate deficiency cause identical hematologic picture, but only B12 deficiency causes neurologic complications.

Feature	B12 Deficiency	Folate Deficiency
Common causes	Pernicious anemia (anti-IF Ab), gastric surgery, veganism, Crohn's (terminal ileum), fish tapeworm, metformin (long-term)	Poor diet (alcoholism, malnutrition), pregnancy, malabsorption, drugs (MTX, phenytoin, trimethoprim), hemolysis (high demand)
Neurologic Sx	Subacute combined degeneration: posterior column (proprioception/vibration) + lateral column (spasticity/UMN) — irreversible if late	None (folate does not protect neurologic myelin)
Serology	↓ B12 (<200 pg/mL), ↑ methylmalonic acid (MMA) & homocysteine — MMA ↑ is specific to B12 def	↓ RBC folate (<150 ng/mL), ↑ homocysteine only (MMA normal)
PBS findings	Macro-ovalocytes, hypersegmented neutrophils (≥5% with 5 lobes, or any with 6+ lobes), anisocytosis
BM findings	Giant metamyelocytes, megaloblastic erythropoiesis (open chromatin, large nuclei)
Treatment	IM cyanocobalamin 1000 µg daily ×7 days → weekly ×4 → monthly (lifelong for pernicious anemia). Oral B12 1000–2000 µg/day effective if no IF deficiency.	Folic acid 5 mg/day PO × 4 months (treat underlying cause)

⚠️ Critical Warning: Never treat B12 deficiency with folate alone. Giving folate to a B12-deficient patient improves the hematologic picture but can precipitate or worsen neurological deterioration (corrects the blood but not the neuropathy). Always check both B12 and folate simultaneously.

Pernicious Anemia

Autoimmune gastritis (type A) → antibodies against parietal cells (anti-parietal cell Ab, 90% sensitive but not specific) and intrinsic factor (anti-IF Ab, 60% sensitive but highly specific). Associated with other autoimmune diseases (Hashimoto, Addison, vitiligo). Lifelong B12 replacement required. Screen for gastric adenocarcinoma (3× increased risk) and gastric carcinoid.

2.5 Sideroblastic Anemia

Characterized by ring sideroblasts in bone marrow (iron-laden mitochondria around nucleus, forming a ring on Prussian blue stain). Ineffective erythropoiesis with iron overload.

Type	Causes	Treatment
Congenital (X-linked)	ALAS2 mutation (delta-aminolevulinic acid synthase 2)	Pyridoxine (B6) — may respond partially
Acquired — Clonal (MDS-RS)	SF3B1 mutation — most common (80% of refractory anemia with ring sideroblasts)	Luspatercept (TGF-β trap) — FDA approved 2020; transfusion support
Acquired — Reversible	Alcohol (most common cause), isoniazid (INH), chloramphenicol, lead poisoning, copper deficiency, zinc toxicity	Remove offending agent; pyridoxine for INH-induced

🔑 Board Tip: Ring sideroblasts + bimodal RBC population on PBS (dimorphic picture) = sideroblastic anemia. Look for history of alcohol use (most common reversible cause) or INH therapy (treat with pyridoxine). Basophilic stippling on PBS = lead poisoning (also causes sideroblastic-type picture with ALA dehydratase inhibition).

📚 Key References — Anemia

ASH 2021 — Guidelines on iron deficiency anemia
BSH 2014 — Investigation and management of megaloblastic anemia
BELIEVE Trial (NEJM 2020) — Luspatercept vs placebo in MDS-RS: 38% vs 13% transfusion independence at 24 weeks
Dr. Parivat Thitiarayavich (Thammasat, 2026) — Hemato Berlin: Anemia approach

3. Hemolytic Anemias

Hemolysis is defined as premature destruction of RBCs (normal lifespan 120 days). Classified as intravascular (within blood vessels) or extravascular (in reticuloendothelial system — spleen/liver). Both elevate LDH and indirect bilirubin; intravascular additionally causes hemoglobinuria, hemoglobinemia, and reduced haptoglobin.

3.1 Approach to Hemolysis

Lab Test	Intravascular Hemolysis (IVH)	Extravascular Hemolysis (EVH)
Serum haptoglobin	↓↓ (markedly low or absent)	↓ (mildly low)
Free plasma hemoglobin	↑↑ (pink plasma)	Normal
Hemoglobinuria	Present (red/brown urine)	Absent
Hemosiderinuria	Present (in chronic IVH — PNH)	Absent
LDH	↑↑↑ (markedly elevated)	↑ (mildly elevated)
Indirect bilirubin	↑	↑↑
Reticulocyte count	↑ (compensatory)	↑ (compensatory)
Examples	PNH, TTP/HUS, mechanical valve hemolysis, transfusion reaction, G6PD + oxidant stress	Warm AIHA, hereditary spherocytosis, sickle cell, thalassemia

🎯 AIHA Classification

Warm AIHA (IgG, 37°C) → extravascular hemolysis; DAT positive (IgG ± C3)
Cold agglutinin disease (IgM, 4°C) → activates complement → intravascular (C3-mediated); DAT positive (C3 only)
Mixed AIHA → both IgG and IgM; severe; DAT positive for both
Cold-reactive IgG (PCH) → Paroxysmal cold hemoglobinuria; IgG Donath-Landsteiner Ab; syphilis/viral infection in children

3.2 Warm AIHA

Most common type (~80%). Mediated by IgG autoantibodies reactive at 37°C against RBC antigens (usually Rh system). Extravascular hemolysis in spleen.

Causes

Idiopathic (50%)
Secondary: SLE (most common autoimmune cause), CLL (10–15% develop AIHA), lymphoma, drugs (methyldopa, penicillin, cephalosporins, fludarabine)

Diagnosis

DAT (Direct Antiglobulin Test / Direct Coombs): Positive for IgG (±C3)
PBS: spherocytes, polychromasia, nucleated RBCs
LDH ↑, indirect bilirubin ↑, haptoglobin ↓

Treatment

Line	Treatment	Response Rate	Notes
1st line	Prednisone 1 mg/kg/day	80% initial response; 15–20% durable remission	Taper over 3–6 months; maintain on lowest effective dose
2nd line	Rituximab (anti-CD20) 375 mg/m² weekly ×4	70–80%	First choice for relapsing/refractory; also used with steroid upfront (RCT data)
2nd line	Splenectomy	60–70% durable remission	2nd line option; vaccinate ≥2 weeks before (S. pneumoniae, H. influenzae, meningococcus)
3rd line	Azathioprine, mycophenolate, cyclosporine, danazol	Variable	Used as steroid-sparing agents
Refractory	Fostamatinib (SYK inhibitor), rilzabrutinib (BTK inhibitor)	40–50%	Emerging therapies for refractory warm AIHA

🔑 Transfusion in AIHA: Avoid transfusion unless life-threatening (Hb <6–7 g/dL with hemodynamic instability). The autoantibody reacts with all donor RBCs — crossmatch is "incompatible" for all. Give "least incompatible" blood if essential. Transfuse slowly with close monitoring.

3.3 Cold Agglutinin Disease (CAD)

Mediated by IgM autoantibodies reactive at cold temperatures (4°C). IgM fixes complement → C3 deposits on RBCs → hemolysis in liver (Kupffer cells) ± intravascular lysis.

Causes

Primary CAD: clonal B-cell disorder (VH4-34 gene rearrangement; similar to MZL/lymphoplasmacytic lymphoma)
Secondary: Mycoplasma pneumoniae (anti-I antibody), EBV mononucleosis (anti-i antibody), lymphoma/CLL

Diagnosis

DAT: C3 positive, IgG negative
Cold agglutinin titer: ≥1:64 at 4°C
PBS: RBC agglutination (clumped RBCs) — can cause falsely high MCV and falsely low RBC count
Symptoms: acrocyanosis, Raynaud's phenomenon in cold; hemoglobinuria after cold exposure

Treatment

Cold avoidance — most important non-pharmacologic measure; warm IV fluids if needed
Rituximab ± bendamustine — first-line pharmacologic (targets clonal B-cells producing IgM)
Sutimlimab (anti-C1s complement inhibitor) — FDA approved 2022 for primary CAD; blocks classical complement activation; reduces transfusion need
Steroids and splenectomy: largely ineffective in CAD (unlike warm AIHA)
Plasma exchange: temporary bridge (removes IgM which is intravascular)

3.4 Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is a clonal disorder of hematopoietic stem cells caused by a somatic mutation in the PIG-A gene → deficiency of GPI-anchored proteins (CD55 = DAF, CD59 = MAC-inhibitory protein) → unregulated complement activation → chronic intravascular hemolysis.

Clinical Triad

Intravascular hemolysis: morning hemoglobinuria (dark urine on waking — complement activated during sleep), pancytopenia
Thrombosis: unusual sites — Budd-Chiari syndrome (hepatic vein), mesenteric vein, cerebral venous sinus, dermal veins; due to platelet/monocyte activation by complement
Bone marrow failure: close association with aplastic anemia (AA); ~25% of AA have PNH clone; ~30% of PNH have hypoplastic marrow

Diagnosis

Flow cytometry (gold standard): absence of CD55 and CD59 on RBCs and granulocytes; report PNH clone size
DAT: Negative (complement-mediated, not antibody-coated)
Ham test / sugar water test: historical, no longer used

Treatment — Complement Inhibitors

Drug	Target	Route	Trial / Approval	Key Feature
Eculizumab	C5 (terminal complement)	IV q2 weeks	TRIUMPH (NEJM 2006); FDA 2007	Pioneer C5 inhibitor; meningococcal vaccine required 2 weeks before; lifelong therapy; does NOT cure marrow failure
Ravulizumab	C5	IV q8 weeks	ALXN1210-PNH-301; FDA 2019	Long-acting eculizumab; superior dosing convenience; non-inferior efficacy; preferred over eculizumab
Iptacopan	Factor B (proximal complement)	PO BID	APPLY-PNH; FDA 2023	First oral PNH therapy; addresses residual extravascular hemolysis (C3-mediated) seen with C5 inhibitors
Danicopan	Factor D (proximal)	PO TID	ALPHA Study; FDA 2024	Add-on to C5 inhibitor for breakthrough hemolysis

🔑 PNH + Aplastic Anemia: If PNH clone >50% AND aplastic anemia present → treat with complement inhibitor. If small PNH clone with aplastic anemia → IST (ATG + cyclosporine) or allogeneic SCT. Allogeneic SCT is the only curative option for PNH.

3.5 Microangiopathic Hemolytic Anemia (MAHA) — TTP / HUS

MAHA is defined by the presence of schistocytes on PBS + evidence of hemolysis. Always consider TTP as a life-threatening emergency requiring immediate diagnosis and treatment.

Feature	TTP	HUS (Typical)	aHUS
Pathogenesis	ADAMTS13 deficiency (<10%): auto-Ab in immune TTP; or severe deficiency in congenital TTP (Upshaw-Schulman)	Shiga toxin (STEC O157:H7) → endothelial damage → complement activation	Complement dysregulation (CFH, CFI, MCP, C3, CFB mutations)
Renal involvement	Mild (10–30%)	Severe AKI (dominant feature)	Severe AKI
Neurologic	Prominent (confusion, seizures, focal deficits)	Usually mild	Variable
Diarrhea	Absent	Bloody diarrhea (prodrome)	Absent
ADAMTS13 activity	<10% (diagnostic)	Normal (usually >10%)	Normal/mildly reduced
Treatment	Plasma exchange (PEX) STAT + immunosuppression (steroids ± rituximab); caplacizumab as adjunct (anti-vWF nanobody)	Supportive + eculizumab in severe cases; avoid antibiotics (↑ toxin release)	Eculizumab/ravulizumab (complement inhibitor)

⚠️ TTP Emergency: Do NOT wait for ADAMTS13 results. If MAHA + thrombocytopenia without alternative explanation → start PEX immediately. Mortality with untreated TTP = 90%; with PEX = 10–20%. Platelet transfusion is CONTRAINDICATED in TTP (fuels thrombosis). Caplacizumab (anti-vWF) added to PEX + steroids reduces time to platelet normalization and recurrence (HERCULES trial, NEJM 2019).

3.6 Hereditary Hemolytic Anemias — Spherocytosis & G6PD

Feature	Hereditary Spherocytosis (HS)	G6PD Deficiency
Inheritance	AD (75%); AR (25%)	X-linked recessive (males affected; females carriers)
Defect	Spectrin, ankyrin, band 3, protein 4.2 mutations → loss of RBC membrane → spherocyte formation	G6PD enzyme deficiency → cannot regenerate NADPH → RBCs vulnerable to oxidative stress
PBS	Spherocytes + polychromasia; RBCs look small and dense; no central pallor	Normal baseline; during crisis: bite cells, blister cells, Heinz bodies (with supravital stain)
Triggers of hemolysis	Infections (aplastic crisis with Parvovirus B19), splenomegaly	Infections, fava beans, primaquine, dapsone, nitrofurantoin, sulfamethoxazole
Lab	Positive osmotic fragility test; EMA binding test (flow cytometry — preferred)	G6PD enzyme activity assay (may be falsely normal during acute crisis — reticulocytes have higher activity)
DAT	Negative	Negative
Treatment	Folic acid supplementation; splenectomy for moderate-severe (reduces hemolysis, does not correct defect)	Avoid triggers; supportive during crisis; transfusion if severe

🔑 Parvovirus B19 Aplastic Crisis: In hereditary hemolytic anemias (HS, SCD, thalassemia), Parvovirus B19 infects erythroid progenitors → sudden cessation of erythropoiesis → severe anemia without reticulocytosis (reticulocyte count drops to near zero) → aplastic crisis. Lasts 7–10 days. Treat with transfusion and supportive care; IVIG for immunocompromised.

📚 Key References — Hemolytic Anemias

ASH 2021 — Diagnosis and management of AIHA
International PNH Interest Group (I-PIG) 2022 — PNH treatment algorithm
APPLY-PNH (NEJM 2021) — Iptacopan for PNH
HERCULES (NEJM 2019) — Caplacizumab for TTP
Dr. Pisa Phiphitaporn (KKU, 2026) — Hemolysis labs: IVH vs EVH, DAT interpretation

4. Hemoglobinopathies

Hemoglobinopathies include thalassemias (quantitative Hb chain defects) and structural Hb variants (qualitative changes — HbS, HbE, HbC). These are among the most common genetic disorders worldwide, with particularly high prevalence in Southeast Asia, Africa, and the Mediterranean.

4.1 Thalassemia — Classification Overview

Type	Gene/Chain Affected	Genotype	Clinical Severity	Key Feature
Alpha-thal silent carrier	1 alpha gene deleted (-α/αα)	αα/-α (heterozygous)	Silent; no anemia	Normal CBC, normal Hb electrophoresis
Alpha-thal trait	2 alpha genes deleted	--/αα or -α/-α	Mild microcytic anemia	HbH not present; MCV ↓; normal Hb A2
HbH disease	3 alpha genes deleted (--/-α)	--/-α	Moderate hemolytic anemia (Hb 7–10)	HbH (β4 tetramers) on Hb electrophoresis; Heinz bodies; splenomegaly
Hb Bart hydrops fetalis	4 alpha genes deleted (--/--)	--/--	Incompatible with extrauterine life	Hb Bart (γ4) = 90%; high oxygen affinity; severe tissue hypoxia; hydrops fetalis; stillbirth
Beta-thal minor (trait)	One beta gene mutated (β/β⁺ or β/β⁰)	β/β⁺ or β/β⁰	Mild microcytic anemia	HbA2 >3.5% (diagnostic); MCV <75 fL; RBC count paradoxically high
Beta-thal intermedia	Two beta gene mutations (milder)	β⁺/β⁺ or β⁰/β⁺	Moderate anemia; transfusion-independent mostly	Hb 7–10 g/dL; splenomegaly; extramedullary hematopoiesis; iron overload even without transfusion
Beta-thal major (Cooley's)	Severe/absent beta chains	β⁰/β⁰ or severe mutations	Severe; transfusion-dependent	Presents in infancy; hepatosplenomegaly; thalassemic facies; "hair-on-end" skull X-ray; requires regular transfusions
HbE/beta-thal	HbE mutation + beta-thal mutation	βE/β⁰ or βE/β⁺	Variable: mild to severe	Most common severe thalassemia in SE Asia; Hb 5–10; may require transfusion

4.2 Thalassemia Management

Transfusion Therapy

Target pre-transfusion Hb: 9–10 g/dL (suppresses ineffective erythropoiesis, prevents thalassemic complications)
Use leukocyte-reduced, crossmatch-extended (Rh, Kell phenotype-matched) packed RBCs to prevent alloimmunization
Transfusion interval: typically every 3–4 weeks

Iron Chelation (prevents organ damage from iron overload)

Drug	Route	Key Side Effects	Notes
Deferoxamine	SC/IV infusion 8–12h/night	Ototoxicity (high-freq), retinopathy, growth retardation, Yersinia infection risk	Gold standard; impractical compliance; use in young children <6 years
Deferasirox	PO once daily	GI upset, renal toxicity, hepatotoxicity; monitor Cr and liver enzymes	First-line oral chelator; FDA approved; once-daily compliance advantage
Deferiprone	PO TID	Agranulocytosis (1–2%); arthropathy; monitor ANC weekly	Best cardiac chelation; used in combination for severe cardiac iron overload; stop if ANC <1500

🔑 Iron Overload Monitoring: Serum ferritin >2500 ng/mL = significant organ risk. MRI T2* for cardiac and liver iron quantification: cardiac T2* <20 ms = cardiac iron loading; <10 ms = high risk for heart failure and arrhythmia → intensify chelation (combination therapy). LIC (liver iron concentration) by MRI is the gold standard.

Disease-Modifying Therapy

Drug	Mechanism	Status / Indication
Luspatercept (Reblozyl)	TGF-β ligand trap → promotes terminal erythroid maturation → reduces transfusion burden	BELIEVE Trial (NEJM 2020): 21% reduction in transfusion burden; FDA approved for transfusion-dependent beta-thal; also MDS-RS
Hydroxyurea	Increases HbF production (γ-chain synthesis); reduces sickling and ineffective erythropoiesis	Useful in HbE/beta-thal (may achieve transfusion independence in some); HbSS
Gene therapy (betibeglogene, lovotibeglogene)	Lentiviral vector adding functional HBB gene to autologous HSCs	HGB-207 (NEJM 2022): 89% of patients transfusion-independent; FDA approved 2022 for TDT; curative potential
Allogeneic SCT	Replaces defective HSCs with donor HSCs	Curative; best outcomes in young patients, class 1 (no hepatomegaly, no irregular chelation); HLA-matched sibling preferred

4.3 Sickle Cell Disease (SCD)

Caused by HbS (Glu→Val substitution at position 6 of beta-globin chain). HbSS = most severe; HbSC and HbS/beta-thal are intermediate severity. Sickle cells cause: vascular occlusion, hemolysis, and organ damage.

Acute Complications

Complication	Mechanism / Features	Management
Vaso-occlusive crisis (VOC)	Most common; pain in bones (femur, spine), chest; triggered by dehydration, infection, cold, hypoxia	IV hydration, analgesia (opioids ± NSAIDs), O2 if hypoxic; avoid dehydration
Acute Chest Syndrome (ACS)	New lung infiltrate + fever + respiratory symptoms + hypoxia; caused by fat embolism, infection, in-situ sickling	Exchange transfusion (target HbS <30%), antibiotics (cover atypicals), bronchodilators, incentive spirometry; most dangerous acute complication
Stroke (ischemic)	Children 2–16 years; cerebrovascular disease; annual risk ~1%	Exchange transfusion STAT; chronic transfusion program to maintain HbS <30%; TCD screening annually from age 2
Aplastic crisis	Parvovirus B19 → cessation of erythropoiesis → severe anemia; low retics	Transfusion support; usually self-limited 7–10 days
Splenic sequestration	Children <5 yrs; massive pooling of blood in spleen → rapid splenomegaly + hypovolemic shock	IV fluids + transfusion; splenectomy if recurrent
Priapism	Vaso-occlusion of corpora cavernosa; >4 hours = urological emergency	IV hydration, analgesia, exchange transfusion; urology consultation for aspiration/irrigation if >4h

Disease-Modifying Therapies

Drug	Mechanism	Indication / Evidence
Hydroxyurea	↑ HbF → dilutes HbS → reduces polymerization; also reduces neutrophils, adhesion molecules	Standard of care ≥2 years; reduces VOC by 44%, ACS, mortality (MSH Trial, NEJM 1995)
L-glutamine	Reduces oxidative stress in RBCs	FDA approved 2017; reduces ACS and hospitalizations (NEJM 2018)
Crizanlizumab	Anti-P-selectin mAb → reduces endothelial-RBC-platelet adhesion	FDA approved 2019; reduces VOC rate (SUSTAIN Trial); revoked 2024 — STAND trial failed
Voxelotor	HbS polymerization inhibitor (allosteric Hb modifier)	FDA approved 2019 for Hb increase; withdrawn 2024 after HOPE-KIDS 2 showed no VOC benefit
Gene therapy (exagamglogene, betibeglogene)	CRISPR-Cas9 reactivates HbF (BCL11A editing) or adds functional HBB	FDA approved Dec 2023; curative potential; very expensive

🔑 Functional Asplenia: SCD patients develop functional asplenia by age 5 due to auto-infarction of the spleen. This creates susceptibility to encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis). Preventive measures: daily penicillin prophylaxis through age 5, pneumococcal vaccination, meningococcal vaccination, annual influenza vaccine.

4.4 Thalassemia Long-Term Complications

Organ/System	Complication	Monitoring / Treatment
Heart	Dilated cardiomyopathy, arrhythmias (most common cause of death in TDT)	Annual ECG, ECHO; MRI T2* <20ms → intensify chelation; cardiac T2* <10ms → IV deferoxamine + deferiprone
Liver	Iron overload hepatopathy → cirrhosis; HCV (historical transfusions)	MRI LIC annually; liver function tests; HCV screening/treatment
Endocrine	Hypogonadism (most common endocrine), growth hormone deficiency, hypothyroidism, DM (from pancreatic iron), hypoparathyroidism (hypocalcemia, tetany)	Annual endocrine screen; HbA1c, thyroid function, IGF-1, sex hormones, calcium/PTH
Bone	Thalassemia osteoporosis (marrow expansion + hypogonadism); pathologic fractures; frontal bossing	DEXA scan biannually; bisphosphonates; Ca/vit D; zoledronic acid
Spleen	Splenomegaly → hypersplenism (↑ transfusion requirements); sequestration	Splenectomy if transfusion requirement >200–250 mL/kg/year; vaccinate 2 weeks prior
Infection	Post-splenectomy sepsis; Yersinia enterocolitica (favored by deferoxamine — acts as siderophore)	Lifelong penicillin post-splenectomy; avoid undercooked shellfish/pork; switch to oral chelator if Yersinia occurs

📚 Key References — Hemoglobinopathies

TIF (Thalassaemia International Federation) Guidelines 2021 — Management of thalassemia
ASH 2019 — Evidence-based management of sickle cell disease
BELIEVE Trial (NEJM 2020) — Luspatercept for transfusion-dependent beta-thal
HGB-207 Gene Therapy (NEJM 2022) — Betibeglogene for TDT
Dr. Parivat Thitiarayavich (Thammasat, 2026) — Thalassemia complications and management

5. Bone Marrow Failure Syndromes & MDS

Bone marrow failure (BMF) occurs when the marrow cannot produce adequate blood cells. This section covers aplastic anemia (AA), pure red cell aplasia (PRCA), and myelodysplastic syndromes (MDS) — the most clinically important BMF entities on the internal medicine board examination.

🔬 Pancytopenia — Diagnostic Algorithm

5.1 Aplastic Anemia (AA)

Aplastic anemia is characterized by pancytopenia + hypocellular bone marrow (<25% cellularity) without evidence of myelodysplasia or infiltrative disease. Pathogenesis: T-cell–mediated immune destruction of hematopoietic stem cells (CD34+) in ~80% (immune-mediated AA).

Severity Classification (Camitta Criteria)

Severity	Criteria (2 of 3 peripheral blood)	BM Cellularity
Non-severe (nSAA)	Does not meet severe criteria	<50% with <30% residual hematopoietic cells
Severe (SAA)	ANC <500/µL, platelets <20,000/µL, reticulocytes <60,000/µL (1% corrected)	<25%
Very Severe (vSAA)	ANC <200/µL + meets SAA platelet/retic criteria	<25%

Treatment Algorithm

Patient	First Line	Second Line	Notes
SAA/vSAA, age ≤40, HLA-matched sibling available	Allogeneic SCT (HLA-matched sibling)	IST if SCT fails	80–90% long-term OS; lower relapse; cures disease
SAA/vSAA, age >40 OR no matched sibling	IST: Horse-ATG + Cyclosporine + Eltrombopag	Allo-SCT (MUD) if IST fails	RACE trial (NEJM 2022): eltrombopag upfront → 68% 6-month CR vs 41%; now standard triplet
nSAA, symptomatic	Cyclosporine ± eltrombopag	IST if no response	Watch-and-wait if minimally symptomatic
SAA refractory to horse-ATG	Rabbit-ATG + cyclosporine	Allo-SCT (MUD)	Horse-ATG superior to rabbit-ATG as first line (Scheinberg NEJM 2011)

🔑 Eltrombopag in AA: Eltrombopag (TPO receptor agonist) was originally used for refractory AA and stimulates residual HSCs via c-Mpl receptor. The RACE Trial (NEJM 2022) established eltrombopag + horse-ATG + cyclosporine as standard first-line IST for SAA, achieving 68% CR at 6 months. Monitor for clonal evolution (MDS/AML — rare but important).

⚠️ Workup Before Treatment: Always rule out PNH (flow cytometry — present in ~25% of AA), Fanconi anemia (chromosome fragility test — diepoxybutane; important in young patients), dyskeratosis congenita (telomere length), and myelodysplastic syndrome (morphology + cytogenetics).

5.2 Pure Red Cell Aplasia (PRCA)

PRCA = selective absence of erythroid precursors in bone marrow (absence of pronormoblasts) with normal WBC and platelets. Reticulocyte count is markedly low (<10,000/µL).

Cause	Mechanism	Treatment
Thymoma-associated (primary)	T-cell mediated; autoantibodies against erythroid precursors	Thymectomy (partial response); cyclosporine; IVIG
Parvovirus B19	Infects pronormoblasts (P antigen receptor) → cytolysis → cessation of erythropoiesis; in immunocompromised (HIV, SCT, lymphoma)	IVIG 400 mg/kg/day × 5–10 days; repeat courses for relapse
Epoetin-induced (anti-EPO antibodies)	Neutralizing antibodies against recombinant EPO → cross-react with endogenous EPO	Stop epoetin immediately; immunosuppression; never rechallenge with any ESA
Autoimmune (idiopathic)	Auto-Ab against EPO receptor or erythroid progenitors	Cyclosporine (first line); rituximab; prednisone
Secondary (CLL, NHL, drugs)	Direct lymphocyte/antibody attack; drug-mediated immune	Treat underlying disorder; stop offending drug

5.3 Myelodysplastic Syndromes (MDS) — WHO 2022

MDS are clonal hematopoietic stem cell disorders with cytopenia(s), dysplastic morphology, ineffective hematopoiesis, and risk of transformation to AML. New WHO 2022 classification reorganizes MDS based on morphology, genetics, and blast percentage.

WHO 2022 Classification

Entity	Key Feature	AML Progression Risk
MDS with low blasts (MDS-LB)	<5% BM blasts, <2% PB blasts; dysplasia ≥10% in one lineage	Low
MDS with low blasts and SF3B1 (MDS-SF3B1)	SF3B1 mutation + ring sideroblasts ≥15%; good prognosis	Very low
MDS with del(5q)	Isolated del(5q); female predominance; macrocytic anemia; hypolobulated megakaryocytes	Low; lenalidomide highly effective
MDS with increased blasts-1 (MDS-IB1)	5–9% BM blasts or 2–4% PB blasts	Intermediate-high
MDS with increased blasts-2 (MDS-IB2)	10–19% BM blasts or 5–19% PB blasts or Auer rods	High (near-AML)
MDS/AML	20–29% BM blasts (new category bridging MDS-IB2 and AML)	Very high
MDS with fibrosis (MDS-F)	Reticulin fibrosis ≥grade 2; must exclude MF	Intermediate
Hypoplastic MDS	BM cellularity <25%; overlaps with aplastic anemia (IST responsive)	Variable

IPSS-R Risk Stratification

Risk Category	IPSS-R Score	Median OS	AML Progression (25%)
Very Low	≤1.5	8.8 years	NR
Low	1.5–3	5.3 years	10.8 years
Intermediate	3–4.5	3 years	3.2 years
High	4.5–6	1.6 years	1.4 years
Very High	>6	0.8 years	0.73 years

Treatment by Risk

Risk Category	Primary Treatment	Notes
Lower risk (Very Low/Low/some Intermediate)	Supportive care: transfusion, ESA (epoetin alfa), G-CSF, iron chelation; luspatercept (MDS-SF3B1); lenalidomide (del5q)	Goal: manage cytopenias, improve QOL; reserve SCT for progression
Higher risk (High/Very High)	Azacitidine (HMA) — prolongs OS; or decitabine; allogeneic SCT if fit	Azacitidine 75 mg/m²/day SC ×7 days, every 28d; AZA-001 Trial (Lancet 2009): OS 24.5 vs 15 months vs CCR
Higher risk — new options	Azacitidine + venetoclax (BCL-2 inhibitor); magrolimab (anti-CD47); IDH1/2 inhibitors for mutant MDS	Emerging combinations; several FDA approvals expected 2024–2025

🔑 del(5q) Syndrome: Female patient, macrocytic anemia, normal/elevated platelets, hypolobulated megakaryocytes on BM, isolated del(5q) on cytogenetics → Lenalidomide 10 mg/day × 21 days/cycle → 67% transfusion independence, 45% complete cytogenetic remission (MDS-003 Trial, NEJM 2006). This is a board-favorite high-yield topic.

📚 Key References — BMF/MDS

WHO Classification of Haematolymphoid Tumours 2022 (5th edition)
ELN 2022 — Recommendations for MDS management
RACE Trial (NEJM 2022) — Eltrombopag + horse-ATG for SAA
AZA-001 (Lancet Oncol 2009) — Azacitidine vs CCR in higher-risk MDS
MDS-003 (NEJM 2006) — Lenalidomide for del(5q) MDS
BELIEVE (NEJM 2020) — Luspatercept in beta-thal and MDS-RS

6. Bleeding Disorders

Bleeding disorders result from defects in primary hemostasis (platelet plug — platelet disorders, vWD) or secondary hemostasis (coagulation cascade — hemophilia, acquired factor deficiencies). Clinical pattern guides diagnosis before laboratory workup.

🧬 Coagulation Cascade — Clinical Correlation

6.1 Approach to the Bleeding Patient

Feature	Primary Hemostasis Defect (Platelet/vWD)	Secondary Hemostasis Defect (Coagulation)
Bleeding type	Mucosal: epistaxis, gingival, menorrhagia, GI bleed, petechiae, purpura	Deep tissue: muscle hematoma, hemarthrosis, retroperitoneal bleed
Onset after injury	Immediate (platelet plug fails quickly)	Delayed (clot forms then lyses — no stable fibrin)
Petechiae	Present (thrombocytopenia, platelet dysfunction)	Absent (coagulation disorders don't affect capillary plugs)
Labs	↓ platelets or abnormal PFA-100 / platelet aggregation; PT/aPTT normal	PT ↑ and/or aPTT ↑; platelets normal
Examples	ITP, TTP, von Willebrand disease, aspirin effect, uremic platelet dysfunction	Hemophilia A/B, acquired hemophilia, DIC, liver disease, vitamin K deficiency, supratherapeutic anticoagulation

6.2 Immune Thrombocytopenia (ITP)

ITP is autoimmune destruction of platelets via anti-platelet IgG antibodies (GPIIb/IIIa, GPIb/IX). Diagnosis of exclusion: isolated thrombocytopenia with normal WBC/Hb/smear (except large platelets), no alternative cause.

Phase	Definition	Treatment Threshold
Newly diagnosed	<3 months	Treat if plt <30,000 OR bleeding
Persistent	3–12 months (not achieved remission)	Same; add 2nd line if no CR with steroids
Chronic	>12 months	Treat if plt <30,000 or symptomatic
Refractory	Fails splenectomy + ≥2 lines	Individualized; TPO-RAs, rituximab

Treatment Ladder

Line	Treatment	Response / Duration
1st line	Prednisone 1 mg/kg/day × 3–4 weeks then taper; or dexamethasone 40 mg/day × 4 days	80% initial; only 20–30% durable
Emergency (plt <10 + bleeding)	IVIG 1 g/kg × 1–2 days + IV methylprednisolone 1 g/day × 3 days ± platelet transfusion (if life-threatening)	IVIG: platelet rise in 24–72h; temporary
2nd line	Rituximab 375 mg/m² weekly ×4; or splenectomy	Rituximab: 40–60% response, 20% durable remission; splenectomy: 65–70% durable remission
TPO receptor agonists	Eltrombopag 50 mg PO daily; romiplostim SC weekly; avatrombopag	80% response; requires maintenance; do not cure; risk of BM fibrosis (rare)
Novel agents	Fostamatinib (SYK inhibitor); rilzabrutinib (BTK inhibitor); efgartigimod (FcRn inhibitor — reduces IgG)	Emerging options for refractory ITP

🔑 H. pylori and ITP: Always test for H. pylori in ITP (urea breath test or stool antigen). Eradication of H. pylori improves platelet count in 40–50% of H. pylori-positive ITP patients, particularly in Asian populations. This is a low-cost, low-risk intervention that should precede splenectomy in most cases.

6.3 Von Willebrand Disease (vWD)

Most common inherited bleeding disorder (1% prevalence). vWF has dual roles: (1) platelet adhesion to subendothelium via GPIb; (2) carrier for factor VIII (extends FVIII half-life). vWD causes both mucosal bleeding and prolonged aPTT (reduced FVIII).

Type	Prevalence	Defect	vWF Ag	vWF Activity	FVIII	Ag:Act Ratio	Treatment
Type 1 (mild)	75–80%	Partial quantitative ↓	↓	↓	Normal/↓	≥0.7 (normal)	DDAVP (desmopressin) — releases vWF from endothelial Weibel-Palade bodies
Type 2A	10–15%	Loss of large multimers	Normal/↓	↓↓	Normal	<0.7	vWF concentrate; DDAVP less effective
Type 2B	5%	Gain-of-function: vWF binds GPIb spontaneously → platelet clumping → loss of large multimers + thrombocytopenia	Normal/↓	↓	Normal	<0.7	vWF concentrate; DDAVP contraindicated (worsens thrombocytopenia)
Type 2M	Rare	↓ platelet-binding function, multimers intact	Normal/↓	↓	Normal	<0.7	vWF concentrate
Type 2N	Rare	↓ FVIII binding; mimics mild hemophilia A	Normal	Normal	↓↓	Normal	vWF concentrate (restores FVIII carrier)
Type 3	1–5%	Complete absence of vWF	Absent	Absent	↓↓↓	—	vWF concentrate; DDAVP ineffective

🔑 DDAVP (Desmopressin): Works by releasing stored vWF from endothelial cells (Weibel-Palade bodies). Used for Type 1 vWD and mild hemophilia A. Dose: 0.3 µg/kg IV. Tachyphylaxis occurs after 2–3 doses (stores depleted). Causes hyponatremia via V2 receptor (antidiuretic effect) — restrict fluids. Contraindicated in: Type 2B vWD, severe renal disease, young children (seizure risk).

6.4 Hemophilia A & B

Feature	Hemophilia A	Hemophilia B (Christmas Disease)
Deficient factor	Factor VIII (FVIII)	Factor IX (FIX)
Gene	F8 gene (X-linked; Xq28)	F9 gene (X-linked; Xq27)
Prevalence	1:5,000 male births (80% of hemophilia)	1:30,000 male births (20% of hemophilia)
Lab	aPTT ↑; PT normal; FVIII level ↓	aPTT ↑; PT normal; FIX level ↓
Severity	Mild: >5%; Moderate: 1–5%; Severe: <1% (spontaneous bleeds)
Treatment — on-demand	Recombinant FVIII concentrate (target 80–100% for major bleed); DDAVP for mild	Recombinant FIX concentrate; DDAVP NOT effective for Hemo B
Prophylaxis	Extended half-life (EHL) FVIII: efmoroctocog alfa, rurioctocog alfa pegol — q3–4 days dosing	EHL FIX: eftrenonacog alfa, albutrepenonacog alfa — weekly to q2-week dosing
Non-factor prophylaxis	Emicizumab (bispecific Ab bridges FIXa-FX, mimics FVIIIa) — SC q1-4 weeks; works regardless of inhibitor status	—
Gene therapy	Fitusiran (anti-antithrombin RNA); valoctocogene roxaparvovec (AAV5-FVIII) FDA approved 2023	Etranacogene dezaparvovec (AAV-FIX Padua) FDA approved 2022

🔑 Inhibitors in Hemophilia: ~30% of severe hemophilia A and 3–5% of hemophilia B develop inhibitors (neutralizing antibodies against infused factor). Screening: Bethesda assay (inhibitor titer in Bethesda Units — BU). Treatment of bleeding with inhibitors: recombinant FVIIa (NovoSeven) or aPCC (FEIBA) — bypass agents. Immune tolerance induction (ITI): high-dose factor infusion to eradicate inhibitor.

6.5 Acquired Hemophilia A (AHA)

AHA is caused by spontaneous autoantibodies against Factor VIII in a previously hemostatically normal individual. Rare but life-threatening. Median age: 60–70 years. Associated with: postpartum (6%), malignancy (15%), autoimmune disease (17%), drugs, idiopathic (50%).

Diagnosis

Unexplained bleeding (soft tissue, muscle, retroperitoneum, mucosal) in patient with no prior bleeding history
Isolated aPTT prolongation that does not correct with 1:1 mixing (incubated 2h at 37°C)
Low FVIII activity + measurable FVIII inhibitor titer (Bethesda assay)

Treatment

Goal	Agent	Notes
Hemostasis (acute bleed)	Recombinant FVIIa (NovoSeven) 90 µg/kg q2–3h; or aPCC (FEIBA) 50–100 U/kg q8–12h	Bypass agents preferred — inhibitor renders FVIII replacement ineffective at standard doses
Hemostasis — alternative	Emicizumab (off-label but increasingly used)	Effective even with high-titer inhibitors; lower thrombotic risk than aPCC
Inhibitor eradication	Prednisone 1 mg/kg/day ± rituximab 375 mg/m² ×4 (first line per EACH registry)	CR achieved in ~87% with steroids; rituximab added for high titer or failure
Second line	Cyclophosphamide 2 mg/kg/day; or mycophenolate	Used if steroids ± rituximab fail

🔑 Board Favorite Topic: AHA classic presentation: elderly patient (or postpartum woman) with sudden-onset large soft tissue hematoma, NO prior bleeding history, isolated aPTT prolongation that does NOT correct on mixing study. Do NOT transfuse FFP (FVIII is too dilute and inhibitor neutralizes it). Start bypass agent immediately.

6.6 Disseminated Intravascular Coagulation (DIC)

DIC is uncontrolled systemic activation of coagulation → simultaneous thrombosis AND consumption coagulopathy → bleeding + organ failure. Not a primary diagnosis — always has a precipitating cause.

Common Triggers (STOP Making New Thrombi)

Sepsis (gram-negative most common; endotoxin activates TF pathway)
Trauma / TBI (brain tissue factor release)
Obstetric (abruptio placentae, amniotic fluid embolism, eclampsia, HELLP, retained fetus)
Pancreatitis (acute severe)
Malignancy (especially APL — promyelocytes release TF; adenocarcinomas)
Necrotizing infections, snake venom
Transfusion reactions (hemolytic)

ISTH DIC Score (for overt DIC)

Parameter	Score 0	Score 1	Score 2	Score 3
Platelet count	>100,000	50–100,000	<50,000	—
PT prolongation	<3 sec	3–6 sec	>6 sec	—
Fibrinogen	>1 g/L	<1 g/L	—	—
D-dimer	No increase	Moderate increase	Strong increase	—

Score ≥5 = compatible with overt DIC. Score <5 = non-overt DIC (monitor).

Treatment

Treat the underlying cause — essential and most important
FFP (Fresh Frozen Plasma): for active bleeding with prolonged PT/aPTT; contains all coagulation factors
Cryoprecipitate: fibrinogen <1 g/L; contains fibrinogen, FVIII, vWF, XIII, fibronectin
Platelet transfusion: if plt <50,000 with active bleeding or <20,000 prophylactically
Heparin: controversial; may be used in thrombosis-dominant DIC (e.g., purpura fulminans); avoid in bleeding-dominant DIC
Antifibrinolytics (tranexamic acid): generally contraindicated in DIC (risk of widespread thrombosis); may be used in hyperfibrinolysis-dominant states (some obstetric DIC, APL)

🔑 APL + DIC: Acute promyelocytic leukemia (APL) causes life-threatening DIC from tissue factor and annexin II on promyelocyte granules. Start ATRA (all-trans retinoic acid) immediately upon clinical suspicion (even before PML-RARA confirmation) — ATRA differentiates promyelocytes, resolving DIC. Transfuse aggressively: goal fibrinogen >1.5 g/L, platelets >50,000, PT ratio <1.5.

📚 Key References — Bleeding Disorders

ASH 2019 — Guidelines for ITP management
ISTH 2016 — Von Willebrand disease diagnosis and treatment
WFH Guidelines 2020 — Management of hemophilia (3rd edition)
EACH2 Registry — Acquired hemophilia A treatment outcomes
HAVEN-3 (NEJM 2018) — Emicizumab prophylaxis in Hemophilia A with inhibitors
Dr. Parivat Thitiarayavich (Thammasat, 2026) — Acquired hemophilia A approach

7. Thrombosis & Anticoagulation

Venous thromboembolism (VTE) — DVT and PE — affects 1–2/1,000 people/year and is the third most common cardiovascular disease. Understanding thrombophilia, anticoagulant pharmacology, and HIT is essential for the internist and hematologist.

7.1 Venous Thromboembolism — DVT & PE

Virchow's Triad

Component	Clinical Correlates
Stasis	Immobility, long-haul flight, cardiac failure, post-surgical, limb cast
Endothelial injury	Trauma, surgery, chemotherapy (cisplatin), IV catheters
Hypercoagulability	Inherited thrombophilia, malignancy, pregnancy, OCP, antiphospholipid syndrome, inflammatory disorders

VTE Risk Assessment — Provoked vs Unprovoked

Category	Definition	Recurrence Risk	Duration of Anticoagulation
Provoked — Major transient	Surgery >30 min, hospitalization >3 days, fracture/cast within 3 months	Low (~1%/yr)	3 months
Provoked — Minor transient	Long-haul flight, OCP/HRT, minor injury, pregnancy	Low-intermediate (~3%/yr)	3 months (OCP/HRT: consider stopping)
Unprovoked	No identifiable provoking factor	High (~5–8%/yr)	Extended (at least 3 months; consider indefinite)
Cancer-associated	Active malignancy at time of VTE	Very high (~15–20%/yr on treatment)	Indefinite while cancer active; LMWH or DOAC
Inherited thrombophilia	Antithrombin, protein C/S deficiency; Factor V Leiden homozygous; antiphospholipid Ab	High	Consider extended; individualize

Cancer-Associated Thrombosis

Rivaroxaban and apixaban are preferred over LMWH (dalteparin) for most cancer-associated VTE (SELECT-D, HOKUSAI VTE Cancer, CARAVAGGIO trials)
Exception: GI/GU malignancy with high bleeding risk → prefer LMWH (lower GI bleed risk with DOACs controversial)
Tinzaparin/dalteparin remain alternatives in high-bleed-risk cancers

7.2 Inherited Thrombophilia

Thrombophilia	Prevalence (General / VTE)	VTE Risk Increase	Lab Diagnosis
Factor V Leiden (FVL)	5% / 20–25%	Hetero: 3–7×; Homo: 50–80×	PCR or functional APC resistance; confirm with genetic test
Prothrombin G20210A	2–3% / 6%	Hetero: 2–3×; Homo: >10×	PCR (cannot diagnose by functional assay)
Antithrombin (AT) deficiency	0.02–0.2% / 1–3%	5–20×	Functional AT activity (<80%); check when not on heparin
Protein C deficiency	0.2–0.4% / 3%	5–10×; warfarin skin necrosis risk	Functional protein C activity; check off anticoagulation
Protein S deficiency	0.1–0.5% / 3%	3–10×; increased in pregnancy, OCP, infection	Free protein S antigen & functional; check off anticoagulation, not during pregnancy
Homocysteinemia	5–10% / 10%	2–3× (modest)	Fasting plasma homocysteine; MTHFR mutation (less clinically significant alone)

🔑 When to Test for Thrombophilia: Test in: (1) unprovoked VTE at age <50; (2) unusual site (cerebral, mesenteric, portal, hepatic vein); (3) recurrent VTE; (4) strong family history; (5) VTE during pregnancy/OCP. Do NOT test during acute thrombosis or on anticoagulation (protein C/S and AT affected by therapy). Test at least 3 months after completing anticoagulation. Note: testing rarely changes duration of anticoagulation for unprovoked VTE.

7.3 Antiphospholipid Syndrome (APS)

APS = acquired thrombophilia with clinical + laboratory criteria (Sapporo/Sydney criteria). Most important acquired cause of thrombosis in young patients.

2023 ACR/EULAR Classification Criteria

Domain	Clinical Criteria	Laboratory Criteria
Macrovascular thrombosis	Arterial/venous thrombosis (DVT, PE, stroke, MI) not explained by other cause	≥1 of the following on ≥2 occasions >12 weeks apart: (1) Lupus anticoagulant (functional — dRVVT, SCT); (2) Anti-cardiolipin IgG/IgM >40 GPL/MPL units; (3) Anti-β2GPI IgG/IgM >40 units
Microvascular thrombosis	Livedo reticularis, livedoid vasculopathy, nephropathy (HTN + proteinuria + AKI)
Obstetric APS	≥3 unexplained early pregnancy losses (<10 weeks); ≥1 loss >10 weeks (normal morphology); or premature birth <34 weeks due to severe PIH/placental insufficiency

🔑 Triple Positive APS: LA + anti-cardiolipin + anti-β2GPI all positive ("triple positive") carries the highest thrombotic risk. These patients should be on warfarin (target INR 2–3), NOT DOACs. The TRAPS trial (NEJM 2018) showed rivaroxaban inferior to warfarin in high-risk APS (triple positive) — increased arterial thrombosis.

Catastrophic APS (CAPS)

Rare (<1% of APS), life-threatening: simultaneous thrombosis in ≥3 organs within 1 week with histologic evidence of small vessel thrombosis. Triggers: infection, surgery, stopping anticoagulation. Mortality 37%. Treatment: anticoagulation (heparin) + high-dose steroids + plasma exchange ± IVIG ± rituximab.

7.4 Anticoagulants — Mechanisms, Monitoring & Reversal

Drug	Target	Route	Monitoring	Reversal Agent	Key Considerations
UFH	Thrombin (IIa) + Xa (via AT); binds AT → conformational change	IV/SC	aPTT (1.5–2.5×) or anti-Xa	Protamine sulfate (1 mg per 100 U UFH)	Used in renal failure (not renally cleared); bridging perioperatively; caution: HIT
LMWH (enoxaparin)	Primarily anti-Xa (10:1 anti-Xa:anti-IIa)	SC	Usually none; anti-Xa for renal impairment, obesity, pregnancy	Protamine (partial: 60–75% reversal)	Preferred in pregnancy; avoid if CrCl <30; dose-adjust CrCl 15–30
Warfarin	Vitamin K epoxide reductase (VKOR) → ↓ factors II, VII, IX, X, PC, PS	PO	INR (target 2–3 for most; 2.5–3.5 for mechanical mitral valve)	Vitamin K; FFP; 4-factor PCC (Kcentra) — fastest reversal	Multiple drug/food interactions; narrow TW; requires regular INR monitoring; avoid in pregnancy (teratogenic)
Dabigatran	Direct thrombin (IIa) inhibitor	PO	Routine monitoring not required; TT (most sensitive); ECT	Idarucizumab (Praxbind) — specific monoclonal Ab; immediate reversal	Renal clearance 80%; avoid if CrCl <30; only DOAC renally excreted this significantly; GI side effects
Rivaroxaban	Direct factor Xa inhibitor	PO	Routine not required; calibrated anti-Xa or PT (less reliable)	Andexanet alfa (Andexxa) — specific for all anti-Xa agents; OR 4-factor PCC as alternative	Take with food (↑ bioavailability); once-daily for most indications (twice-daily for treatment dose in first 3 weeks of VTE)
Apixaban	Direct factor Xa inhibitor	PO	Routine not required; calibrated anti-Xa	Andexanet alfa; 4-factor PCC	Twice-daily; lowest GI bleed risk among DOACs; preferred in elderly/renal impairment
Fondaparinux	Selective Xa inhibitor (indirect via AT)	SC	Anti-Xa level	No specific reversal (recombinant FVIIa off-label)	No risk of HIT (does not bind PF4); used in HIT treatment; avoid CrCl <30

7.5 Heparin-Induced Thrombocytopenia (HIT)

HIT is a prothrombotic disorder caused by IgG antibodies against the PF4-heparin complex. Despite being a thrombocytopenic disorder, HIT is a hypercoagulable state — patients are at high risk for venous AND arterial thrombosis.

4T Scoring (Pre-Test Probability)

Parameter	2 Points	1 Point	0 Points
Thrombocytopenia	>50% fall, nadir ≥20,000	30–50% fall, or nadir 10–19,000	<30% fall, or nadir <10,000
Timing of fall	Days 5–10 (or ≤1 day if prior heparin in 30–100 days)	Consistent but unclear; onset after day 10	≤4 days without prior exposure
Thrombosis	New confirmed thrombosis; skin necrosis; acute systemic reaction post-IV bolus	Progressive/recurrent thrombosis; erythematous skin lesions	None
Other cause of thrombocytopenia	None evident	Possible	Definite

Score interpretation: 0–3 = Low (HIT unlikely, 1–5%); 4–5 = Intermediate; 6–8 = High (>80% probability)

Diagnosis & Treatment

Lab confirmation: Anti-PF4-heparin IgG ELISA (high sensitivity); Serotonin release assay (SRA) or heparin-induced platelet activation (HIPA) = functional gold standard (high specificity)
STOP ALL heparin immediately (including flushes, LMWH, heparin-coated catheters)
Start non-heparin anticoagulant at full therapeutic dose (even without overt thrombosis — HIT itself is thrombogenic):
- Argatroban (direct thrombin inhibitor) — IV; preferred in renal failure; hepatic clearance; causes INR elevation (complicates warfarin transition)
- Fondaparinux (anti-Xa, indirect) — SC; no cross-reactivity with PF4-heparin Ab; widely used
- Bivalirudin (direct thrombin inhibitor) — IV; used in cardiac surgery/PCI setting
- DOACs (rivaroxaban, apixaban) — increasingly used once platelet count stable >150,000
Do NOT give warfarin until platelet count >150,000 (risk of venous limb gangrene from microvascular thrombosis)
Do NOT transfuse platelets (fuels thrombosis)

📚 Key References — Thrombosis

ASH 2021 — Guidelines for VTE treatment (full update)
ISTH 2017 — Diagnosis and management of HIT
ACR/EULAR 2023 — APS classification criteria
TRAPS Trial (NEJM 2018) — Rivaroxaban vs warfarin in high-risk APS
CARAVAGGIO (NEJM 2020) — Apixaban vs dalteparin in cancer VTE

8. Myeloid Neoplasms

Myeloid neoplasms include acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and chronic myeloid leukemia (CML). The WHO 2022 and ICC 2022 classifications represent major updates in molecular-driven disease definition.

🧬 AML — ELN 2022 Genetic Risk Stratification

8.1 Acute Myeloid Leukemia (AML) — Diagnosis & Treatment

AML is defined by ≥20% myeloid blasts in bone marrow or peripheral blood (WHO 2022) OR by specific genetic abnormalities (t(8;21), inv(16), t(15;17) — diagnostic regardless of blast %). New: WHO 2022 introduces "AML with defining genetic abnormalities" without blast % threshold for high-risk mutations (TP53, RUNX1 etc.).

Standard Induction Chemotherapy

Regimen	Protocol	Patient	CR Rate
7+3 (Standard)	Cytarabine 100–200 mg/m² CI ×7 days + Daunorubicin 60–90 mg/m² ×3 days (or idarubicin)	Fit patients ≤75 yrs, without adverse features	65–80%
CPX-351 (Vyxeos)	Liposomal cytarabine:daunorubicin (5:1 ratio)	Secondary AML (t-AML, MDS-related AML), older patients	48% vs 33% CR; OS benefit (NEJM 2017)
AZA + Venetoclax	Azacitidine + Venetoclax (BCL-2 inhibitor)	Unfit/elderly patients (≥75 or comorbidities)	CR 37% vs 18%; OS 14.7 vs 9.6 mo (VIALE-A, NEJM 2020)

Targeted Therapies

Target	Drug	Approval	Use
FLT3 (ITD or TKD)	Midostaurin (FLT3 inhibitor)	FDA 2017 — with 7+3 induction (RATIFY Trial, NEJM 2017)	FLT3-mutated AML; add to induction + consolidation; OS benefit
FLT3	Gilteritinib	FDA 2018 — relapsed/refractory FLT3-mut AML	Monotherapy for R/R; superior to salvage chemo
IDH2	Enasidenib	FDA 2017 — R/R IDH2-mut AML	Watch for IDH differentiation syndrome (similar to ATRA syndrome)
IDH1	Ivosidenib	FDA 2018 — R/R IDH1-mut AML; also MDS	IDH differentiation syndrome risk
CD33	Gemtuzumab ozogamicin (GO)	FDA 2017 — CD33+ AML, favorable/intermediate risk	Added to 7+3 for favorable/intermediate AML; benefit in CBF-AML
BCL-2	Venetoclax	FDA 2018 — with AZA or LDAC for unfit elderly	Standard of care for unfit AML; also used in combinations
Menin	Revumenib, ziftomenib	FDA 2024 — KMT2A-rearranged or NPM1-mutated R/R AML	Novel menin inhibitor for NPM1-mut and KMT2A-rearranged AML

8.2 Acute Promyelocytic Leukemia (APL) — ATRA + ATO Protocol

APL = AML with t(15;17)(q22;q12) → PML-RARA fusion → differentiation block at promyelocyte stage. Once universally fatal; now the most curable leukemia (OS >95% with ATRA + ATO). Emergency: life-threatening DIC and differentiation syndrome.

Diagnosis

PBS: abnormal promyelocytes with bilobed nuclei, heavy granulation, Auer rods (bundles = "faggot cells")
Coagulopathy: elevated PT, aPTT, D-dimer, low fibrinogen — DIC picture
Cytogenetics: t(15;17); FISH/PCR for PML-RARA (fastest confirmation)
Immunophenotype: CD33+, CD34−, HLA-DR−, CD13+ (low/absent CD11b, CD18)

ATRA + ATO Chemotherapy-Free Protocol (Low/Intermediate Risk)

Phase	Regimen	Duration	Target
Induction	ATRA (all-trans retinoic acid) 45 mg/m²/day PO + ATO (arsenic trioxide) 0.15 mg/kg/day IV	Until CR (~ 4–6 weeks)	CR rate >95%; MRD negative by PCR in most
Consolidation	ATRA + ATO (4 cycles: ATO 5 days/week × 4 weeks alternating with ATRA 2 weeks)	~7 months total	MRD negativity by PCR (PML-RARA)
High-risk (WBC >10,000)	ATRA + ATO + Gemtuzumab ozogamicin (GO) or anthracycline-based	Similar consolidation	High WBC = risk of differentiation syndrome and early death

🔑 APL Differentiation Syndrome (formerly ATRA syndrome): Occurs in 10–25% during induction; caused by differentiation of promyelocytes with cytokine release → pulmonary infiltrates, fever, weight gain, fluid retention, hypotension, pericardial/pleural effusion, renal failure. Treatment: Dexamethasone 10 mg IV BID × 3+ days immediately. Do NOT stop ATRA/ATO unless severe respiratory failure. Early recognition is critical — can be fatal.

⚠ ATO Toxicity: QTc prolongation (monitor ECG; avoid concurrent QT-prolonging drugs). Hyperleukocytosis (watch WBC during induction). Hepatotoxicity (check LFTs). Peripheral neuropathy with prolonged use. Electrolyte management: correct K+ >4 mEq/L and Mg²⁺ >1.8 mg/dL before starting ATO.

8.3 Chronic Myeloid Leukemia (CML) — TKI Era

CML is defined by the BCR-ABL1 fusion oncogene (Philadelphia chromosome, t(9;22)(q34;q11)). ABL1 tyrosine kinase is constitutively activated → uncontrolled myeloid proliferation. Phases: chronic phase (CP) → accelerated phase (AP) → blast phase (BP).

Tyrosine Kinase Inhibitors (TKIs)

Generation	Drug	Key Side Effects	Resistance Mutation Covered	Notes
1st	Imatinib (Gleevec) 400 mg/day	Edema, nausea, muscle cramps, hepatotoxicity	None (T315I → resistance)	Pioneer TKI; first-line option; generic available; generic preferred for cost in LMIC
2nd	Dasatinib 100 mg/day	Pleural effusion (25%), pulmonary arterial HTN, QTc prolongation	Most mutations except T315I	Penetrates CNS (preferred for CNS involvement); faster deep molecular response vs imatinib
2nd	Nilotinib 300 mg BID	Hyperglycemia, elevated lipase, QTc prolongation, cardiovascular events (atherosclerosis)	Most mutations except T315I; Y253H/E255K	Fastest MMR achievement; avoid in cardiovascular disease patients
2nd	Bosutinib 400 mg/day	GI toxicity (diarrhea), liver toxicity	Most mutations except T315I, V299L	Option for 2nd-line after imatinib failure
3rd	Ponatinib 45 mg/day	Arterial/venous thrombosis, pancreatitis, hepatotoxicity, HTN	T315I (gatekeeper mutation) and all other BCR-ABL mutations	Reserved for T315I mutation or resistance to 2+ TKIs; serious CV risk — dose-reduce after response (15 mg)
3rd	Asciminib (Scemblix)	Pancreatitis, thrombocytopenia, HTN	T315I (special formulation 200 mg BID)	STAMP inhibitor (binds myristoyl pocket); superior PFS vs bosutinib in 3rd-line (ASCEMBL, NEJM 2021)

Treatment-Free Remission (TFR)

After achieving sustained deep molecular response (MR4.5) for ≥2 years, TKI discontinuation can be attempted (40–60% maintain TFR). Relapses (molecular) respond to TKI re-initiation in >95%. TFR is a major treatment goal in CML. Criteria (ELN 2020): BCR-ABL1 ≤0.01% IS (MR4) maintained ≥3 years on 2nd-gen TKI.

🔑 Monitoring CML Response: Use International Scale (IS) quantitative PCR: BCR-ABL1 IS. Milestones (ELN 2022): Complete hematologic response (CHR) at 3 months; BCR-ABL1 ≤10% IS (major molecular response, MMR) at 6 months; MR4 (<0.01%) at 12 months = optimal. Failure at any milestone → mutational analysis → switch TKI.

8.4 Myeloproliferative Neoplasms (MPN) — PV, ET, MF

The classical BCR-ABL1–negative MPNs include Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Driven by driver mutations: JAK2 V617F (most common), CALR (exon 9), and MPL (thrombopoietin receptor).

Feature	Polycythemia Vera (PV)	Essential Thrombocythemia (ET)	Primary Myelofibrosis (PMF)
Driver mutations	JAK2 V617F 97%; JAK2 exon 12 (3%); always JAK2	JAK2 V617F 55%; CALR 25%; MPL 5%; triple-negative 15%	JAK2 V617F 55%; CALR 25%; MPL 8%; triple-negative 12%
Blood count	Hb ↑↑; Hct ↑ (>49% M, >48% F); leukocytosis; thrombocytosis	Platelets >450×10³ (often >1000); Hb usually normal	Anemia; teardrop cells; leukoerythroblastic; variable plt
WHO 2022 diagnosis	Major: BM hypercellularity + Hb/Hct elevation + JAK2 mutation; minor: ↓ EPO; All 3 major OR 2 major + 1 minor	Plt >450; BM megakaryocyte proliferation; JAK2/CALR/MPL mutation; exclude reactive cause	BM fibrosis + reticulin; megakaryocyte atypia; JAK2/CALR/MPL; exclude other MPN/MDS
Key complications	Thrombosis (major cause of death); erythromelalgia; aquagenic pruritus; portal/hepatic vein thrombosis; transformation to MF/AML	Thrombosis + bleeding (paradoxical at very high plt); microvascular symptoms; rarely transforms to MF/AML	Constitutional symptoms; massive splenomegaly; anemia (transfusion-dependent); portal HTN; blast transformation (20% at 10 yrs)
Treatment	Phlebotomy (target Hct <45%); low-dose aspirin; cytoreduction for high-risk: Hydroxyurea (1st line) or Ruxolitinib (JAK1/2 inhibitor — for HU-refractory/intolerant)	Aspirin ± cytoreduction for high-risk (age >60 or prior thrombosis): HU or anagrelide; low-risk: aspirin alone	DIPSS/MIPSS70 risk stratification; low/intermediate-1: observation; higher risk: Ruxolitinib (reduces spleen, symptoms — COMFORT-I/II); allogeneic SCT (only cure)

🔑 Ruxolitinib in MF: Ruxolitinib (JAK1/2 inhibitor) reduces spleen volume and constitutional symptoms in MF (COMFORT-I, NEJM 2012) but does not eliminate fibrosis or reduce blast transformation. Watch for: dose-dependent anemia and thrombocytopenia, reactivation of TB/HBV/herpes zoster, and "ruxolitinib withdrawal syndrome" (do NOT stop abruptly — taper gradually). New MF agents: fedratinib, pacritinib (for platelets <50K), momelotinib (improves anemia via ACVR1 inhibition).

PV: Aquagenic Pruritus

Severe itching after warm water exposure — caused by mast cell degranulation triggered by basophil-derived histamine. Treatment: antihistamines, SSRIs (paroxetine best evidence), phototherapy (PUVA), alpha interferon, ruxolitinib.

📚 Key References — Myeloid Neoplasms

ELN 2022 — AML diagnosis, risk stratification, and treatment recommendations
WHO 5th Edition 2022 — Classification of haematolymphoid tumours
VIALE-A (NEJM 2020) — AZA + venetoclax for newly diagnosed unfit AML
RATIFY (NEJM 2017) — Midostaurin + 7+3 for FLT3-mutated AML
Lo-Coco APL (NEJM 2013) — ATRA + ATO for non-high-risk APL: chemotherapy-free
ASCEMBL (NEJM 2021) — Asciminib vs bosutinib for CML 3rd line
COMFORT-I/II (NEJM 2012) — Ruxolitinib for MF

9. Lymphoid Neoplasms

Lymphoid neoplasms encompass leukemias (ALL, CLL), lymphomas (NHL, HL), and plasma cell disorders (multiple myeloma). The WHO 2022 classification integrates molecular and immunophenotypic features for more precise disease definition.

🔎 Lymphadenopathy — Diagnostic Approach

9.1 Chronic Lymphocytic Leukemia (CLL)

CLL is the most common leukemia in adults (>50 years) in Western countries. Defined by ≥5,000/µL clonal B lymphocytes (CD5+, CD19+, CD23+, dim CD20, dim surface Ig) in peripheral blood for ≥3 months. If <5,000 = SLL (small lymphocytic lymphoma, tissue disease without circulating lymphocytosis).

Prognostic Factors

Factor	Favorable	Unfavorable
IGHV mutation status	Mutated (>2% from germline) — indolent	Unmutated — aggressive; median OS ~8 years
Chromosomal abnormality	del(13q) alone — best prognosis; normal karyotype	del(17p), TP53 mutation — worst; del(11q) — aggressive
ZAP-70, CD38	ZAP-70 negative, CD38 <30%	ZAP-70 positive, CD38 ≥30%
Rai/Binet stage	Rai 0–1 / Binet A — observation	Rai III–IV (anemia/thrombocytopenia) / Binet C — treatment needed

When to Treat

Active disease criteria (iwCLL 2018): B symptoms, progressive cytopenias (AIHA, ITP), symptomatic splenomegaly, rapidly progressive lymphocytosis (LDT <6 months), bulky lymphadenopathy >10 cm
Lymphocyte count alone is NOT an indication to treat

Treatment — Current Era

Setting	Preferred Regimen	Trial Evidence
Fit, no del(17p)/TP53 mutation	Ibrutinib (BTKi) or Acalabrutinib + obinutuzumab (anti-CD20); or Venetoclax + obinutuzumab (12 cycles, fixed duration)	CLL14 (NEJM 2019): venetoclax+obinutuzumab vs chlorambucil; ELEVATE-TN: acalabrutinib
del(17p) or TP53 mutation	Ibrutinib or Zanubrutinib (next-gen BTKi) — indefinite; venetoclax+obinutuzumab also effective but shorter duration	BTKi preferred (overcomes del17p); FCR ineffective in del17p
Elderly/unfit	Venetoclax + obinutuzumab (time-limited 12 cycles); or ibrutinib monotherapy; or chlorambucil + obinutuzumab	Time-limited venetoclax preferred for MRD-negativity potential
CLL-associated AIHA/ITP	Treat CLL (ibrutinib or rituximab-based); steroids for acute hemolysis; avoid fludarabine (worsens AIHA)	Fludarabine contraindicated in active AIHA (hemolytic flare)

9.2 Diffuse Large B-Cell Lymphoma (DLBCL)

DLBCL is the most common aggressive lymphoma (30–35% of NHL). Potentially curable with immunochemotherapy. Two major cell-of-origin subtypes: GCB (germinal center B-cell, better prognosis) and ABC/non-GCB (activated B-cell, worse prognosis).

International Prognostic Index (IPI)

IPI Factor (each = 1 point)	Score	5-yr OS (R-CHOP era)
Age >60; LDH > normal; ECOG PS ≥2; Stage III–IV; ≥2 extranodal sites	0–1 (Low)	~75–85%
—	2–3 (Intermediate)	~50–65%
—	4–5 (High)	~30–40%

Treatment

Setting	Regimen	Notes
1st line (all stages)	R-CHOP (rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone) × 6–8 cycles	Cures 50–60% of patients overall; standard of care since 1997
High-risk (IPI 3–5) or double-hit	DA-R-EPOCH (dose-adjusted); or R-CHOP + consolidation SCT	MYC + BCL2/BCL6 co-rearrangement ("double-hit") = aggressive; poor R-CHOP response
2nd line (relapsed/refractory)	Salvage (R-ICE, R-DHAP, R-GDP) → high-dose chemo + autologous SCT (ASCT) if chemosensitive	Goal: achieve PR/CR before ASCT
CAR-T cell therapy	Axicabtagene ciloleucel (axi-cel), tisagenlecleucel, lisocabtagene maraleucel	FDA approved for R/R DLBCL after ≥2 lines; ZUMA-7 (NEJM 2022): axi-cel superior to ASCT as 2nd-line for early R/R DLBCL
Bispecific antibodies	Glofitamab (CD20×CD3), Epcoritamab	FDA approved 2023 for R/R DLBCL after ≥2 lines; fixed-duration glofitamab

9.3 Hodgkin Lymphoma (HL)

Classic HL features: Reed-Sternberg cells (large binucleated cells with prominent "owl-eye" nucleoli) in an inflammatory background. Derived from B-cells (CD30+, CD15+, CD20−). Bimodal age distribution (15–35 and >55 years). Highly curable (OS >85% overall).

Classification (WHO 2022)

Subtype	Frequency	Histology	EBV Association
Nodular sclerosis (NSHL)	70%	Collagen bands; lacunar RS cells	10–25%
Mixed cellularity (MCHL)	20–25%	Mixed inflammatory infiltrate; classic RS cells	75%
Lymphocyte-rich (LRHL)	5%	Nodular; RS cells in lymphocyte-rich background	40%
Lymphocyte-depleted (LDHL)	<1%	Few lymphocytes; many RS cells; worst prognosis	75%
Nodular lymphocyte-predominant HL (NLPHL)	5%	LP (lymphocyte predominant "popcorn") cells; CD20+, CD30−, CD15−; EMA+	Rare

Treatment

Stage	Regimen	Notes
Early (Stage I–II, favorable)	ABVD ×2 cycles + involved-field RT (20 Gy)	ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine; avoid bleomycin in elderly (pulmonary toxicity)
Early, unfavorable	ABVD ×4 + RT; or BV-AVD ×4 + RT	BV (brentuximab vedotin, anti-CD30 ADC) replaces bleomycin
Advanced (Stage III–IV)	BV-AVD ×6 cycles (no RT for most)	ECHELON-1 (NEJM 2018): BV-AVD vs ABVD — superior 5-yr PFS (82% vs 75%); now standard in advanced HL
Relapsed/refractory	Salvage → ASCT; Pembrolizumab (anti-PD-1) or nivolumab for R/R post-ASCT or transplant-ineligible	KEYNOTE-204 (Lancet 2021): pembrolizumab vs BV in R/R cHL post-ASCT failure; OS benefit

🔑 Bleomycin Toxicity: Pulmonary toxicity (bleomycin-induced pneumonitis, BIP) is the most serious ABVD side effect — dose-dependent; cumulative dose >400 U/m² major risk. Present with dyspnea, dry cough, bilateral infiltrates. Stop bleomycin immediately if suspected. Consider ABVD → AVD after 2 cycles if PET-negative (omit bleomycin in elderly and bulky disease patients). PET-adapted therapy is current standard.

9.4 Multiple Myeloma (MM)

MM is a clonal plasma cell malignancy (>10% BM plasma cells) with monoclonal protein production and end-organ damage. Incidence increasing; median age 65–70. Related conditions: MGUS → smoldering MM → active MM.

CRAB Criteria (End-Organ Damage → Active MM)

Letter	Criterion	Mechanism / Notes
C — HyperCalcemia	Calcium >11 mg/dL or >1 mg/dL above ULN	RANKL activation by plasma cells → osteoclast activation → bone resorption
R — Renal failure	Creatinine >2 mg/dL or CrCl <40 mL/min	Cast nephropathy (Bence-Jones proteins = light chains), hypercalcemia, amyloid, direct plasma cell infiltration
A — Anemia	Hb <10 g/dL or >2 g below LLN	BM infiltration by plasma cells; EPO suppression; rouleaux formation on PBS
B — Bone lesions	≥1 lytic lesion on CT/PET-CT/MRI; osteoporosis with compression fracture	Osteolytic lesions: "punched-out" lesions on skull X-ray; vertebral compression fractures
+SLiM criteria (2014)	BM plasma cells ≥60%; sFLC ratio ≥100; MRI >1 focal lesion	Biomarkers that predict end-organ damage within 2 years → treat without waiting for CRAB

Treatment Overview

Setting	Standard Regimen	Notes
Transplant-eligible (1st line)	VRd (bortezomib + lenalidomide + dexamethasone) × 4 cycles → ASCT → lenalidomide maintenance	DETERMINATION (NEJM 2022): VRd+ASCT superior to VRd alone
Transplant-eligible, high-risk	Dara-VRd (daratumumab + VRd) → ASCT; or IsaVRd (isatuximab + VRd)	GRIFFIN (JCO 2021): Dara-VRd superior stringent CR and MRD negativity; now preferred by most centers
Transplant-ineligible (1st line)	Dara-VRd or Dara-Rd (daratumumab + lenalidomide + dexamethasone)	MAIA (NEJM 2019): Dara-Rd vs Rd → PFS 61 vs 34 months; superior OS
Relapsed/refractory (RRMM)	Carfilzomib-based; ixazomib-Rd; elotuzumab-Pd; selinexor; anti-BCMA: belantamab mafodotin, idecabtagene vicleucel (CAR-T), ciltacabtagene autoleucel (CAR-T), teclistamab (bispecific)	Anti-BCMA CAR-T: ciltacel CARTITUDE-4 (NEJM 2023): superior PFS vs Pd/DPd in 1-4 prior lines

🔑 Daratumumab (Dara): Anti-CD38 monoclonal antibody. Key AE: infusion reactions (pre-medicate with steroids/antihistamine/acetaminophen) and interference with blood bank crossmatch (CD38 on RBCs — causes false-positive DAT and panagglutination). Alert blood bank before starting daratumumab → phenotype RBCs before first infusion, use dithiothreitol (DTT)-treated panels.

Supportive Care in MM

Issue	Management
Bone disease	Bisphosphonates: Zoledronic acid 4 mg IV q4 weeks (superior to pamidronate); or Denosumab (anti-RANKL) preferred if CrCl <30; monitor jaw osteonecrosis
Hypercalcemia	IV hydration; IV bisphosphonates; calcitonin; corticosteroids
VTE (thalidomide/lenalidomide risk)	Aspirin (low risk); LMWH or warfarin (high risk with 2+ VTE risk factors); rivaroxaban emerging data
Renal impairment	Hydration; avoid NSAIDs/nephrotoxins; bortezomib-based regimen (renally safe); plasmapheresis for cast nephropathy (controversial); dialysis if needed
Infection prophylaxis	Antivirals (acyclovir) with bortezomib (herpes zoster); TMP-SMX for PCP with high-dose dex; vaccination (flu, pneumococcal, COVID)

9.5 Lymphoma Mimics (Reactive Conditions)

Several benign conditions mimic lymphoma clinically and histologically — critical not to over-treat:

Condition	Features	Histology	Diagnosis / Treatment
Kikuchi-Fujimoto Disease	Young Asian women; posterior cervical LAD; fever; self-limited; SLE-like	Histiocytic necrotizing lymphadenitis; no plasma cells; no neutrophils	Self-limiting in 1–4 months; NSAIDs for symptoms; biopsy essential to exclude lymphoma; rare SLE association
Rosai-Dorfman Disease	Massive painless cervical LAD + fever; extranodal (nasal, skin, CNS)	Emperipolesis (lymphocytes within histiocyte cytoplasm — S100+, CD1a−)	Usually self-limiting; surgery/steroids for symptomatic; rare malignant transformation
Castleman's Disease	Unicentric (benign, resect) or multicentric (MCD — fever, organomegaly, cytopenias)	Unicentric: hyaline vascular type; MCD: plasma cell type	Unicentric: surgical excision curative; MCD: Siltuximab (anti-IL-6, FDA approved) or tocilizumab; MCD with HHV-8: treat underlying HIV/KS
Infectious Mononucleosis	EBV infection; teenager/young adult; fever, pharyngitis, posterior cervical LAD, atypical lymphocytes, splenomegaly	Atypical T lymphocytes (CD8+ cytotoxic) in reaction to EBV-infected B cells	Supportive; avoid ampicillin/amoxicillin (maculopapular rash in 80–90%); avoid contact sports (splenic rupture)

📚 Key References — Lymphoid Neoplasms

IMWG 2016 — Diagnostic criteria and response criteria for myeloma
iwCLL 2018 — CLL diagnostic and treatment criteria update
MAIA (NEJM 2019) — Daratumumab + Rd for transplant-ineligible MM
ECHELON-1 (NEJM 2018) — BV-AVD vs ABVD for advanced HL
ZUMA-7 (NEJM 2022) — Axi-cel vs ASCT in early R/R DLBCL
CARTITUDE-4 (NEJM 2023) — Ciltacel CAR-T in RRMM
Dr. Pisa Phiphitaporn (KKU, 2026) — Lymphadenopathy approach, Kikuchi, Rosai-Dorfman, Castleman's

10. Practice Questions & High-Yield Summary

Board-style practice questions covering the most tested hematology topics. Each question mirrors the USMLE Step 3 / Thai Internal Medicine board format. Use these to consolidate knowledge before examination.

10.1 Anemia & Red Cell Disorders — Questions

Q1. A 28-year-old Thai woman presents with fatigue and dysphagia. Examination reveals smooth tongue, koilonychia, and a post-cricoid web on barium swallow. CBC: Hb 7.8 g/dL, MCV 62 fL, RDW 18%, platelets 420×10³/µL. What is the most likely diagnosis and the pre-malignant concern?

Answer: Plummer-Vinson Syndrome (Patterson-Kelly syndrome)

Classic triad: IDA + glossitis/koilonychia + post-cricoid esophageal web → dysphagia. Pre-malignant: esophageal squamous cell carcinoma risk increased 3–4×. Treatment: iron supplementation (often resolves web) ± endoscopic dilation. Repeat endoscopy surveillance recommended. IDA workup: check ferritin (↓↓), serum iron (↓↓), TIBC (↑↑).

Q2. A 65-year-old male has Hb 9.1 g/dL, MCV 78 fL, B12 level 190 pg/mL, folate normal. Methylmalonic acid (MMA) is markedly elevated. Anti-intrinsic factor antibodies are positive. He now presents with new upper and lower extremity paresthesias and difficulty walking. What is the neurological diagnosis and the key management priority?

Answer: Subacute Combined Degeneration of the Spinal Cord (B12 deficiency — Pernicious Anemia)

Subacute combined degeneration affects: (1) posterior columns (loss of proprioception/vibration — sensory ataxia); (2) lateral corticospinal tracts (UMN signs — spasticity, hyperreflexia, Babinski). Anti-IF antibody positive = pernicious anemia. Management: IM cyanocobalamin 1000 µg daily × 7 days → weekly × 4 → monthly lifelong. MMA is specific to B12 deficiency (homocysteine elevated in both B12 and folate deficiency). Do NOT give folate alone — neurological deterioration may worsen. Note: B12 level of 190 pg/mL is borderline; MMA elevation confirms true deficiency.

Q3. A 35-year-old man presents after an acute hemolytic episode triggered by eating fava beans. PBS shows bite cells and blister cells. Heinz bodies seen on crystal violet stain. Haptoglobin is absent. DAT is negative. What enzyme deficiency explains this picture and what is the key board management principle?

Answer: G6PD (Glucose-6-Phosphate Dehydrogenase) Deficiency

X-linked recessive; males affected. Oxidative stress (fava beans, dapsone, primaquine, TMP-SMX, nitrofurantoin, infections) → NADPH depletion → Heinz bodies (denatured Hb) → bite cells (spleen removes Heinz body inclusions) → intravascular hemolysis. Management: (1) Identify and remove trigger; (2) Supportive care — hydration, transfusion if severe (Hb <7 or hemodynamically unstable); (3) Avoid triggering drugs lifelong. Important: G6PD enzyme assay may be falsely normal during acute crisis — young reticulocytes have higher G6PD activity. Repeat assay 2–3 months after crisis for accurate result. DAT is negative (not antibody-mediated).

Q4. A 42-year-old woman with 3-year history of episodic morning dark urine, pancytopenia (Hb 7.8, plt 58K, WBC 2.8), and recent Budd-Chiari syndrome (hepatic vein thrombosis). Flow cytometry shows >50% of RBCs and granulocytes negative for CD55 and CD59. DAT is negative. What is the diagnosis and first-line treatment?

Answer: Paroxysmal Nocturnal Hemoglobinuria (PNH)

Classic PNH triad: intravascular hemolysis (hemoglobinuria) + thrombosis (unusual sites: hepatic, mesenteric, cerebral) + BM failure (pancytopenia). Confirmed by flow cytometry: absence of GPI-anchored proteins (CD55, CD59) on RBCs and granulocytes. Treatment: Eculizumab (anti-C5, FDA 2007) or ravulizumab (preferred — q8w dosing). Must vaccinate against Neisseria meningitidis, S. pneumoniae, H. influenzae ≥2 weeks before starting. Anticoagulation for acute thrombosis. Allogeneic SCT is the only cure (consider if severe aplasia or refractory). New oral option: iptacopan (Factor B inhibitor) — addresses residual EVH.

10.2 Bleeding & Thrombosis — Questions

Q5. A 72-year-old woman with no prior bleeding history presents with a massive right thigh hematoma (not related to trauma). Labs: Hb 7.2 g/dL, platelets 280×10³/µL, PT normal, aPTT 95 seconds. 1:1 mixing with normal plasma does NOT correct aPTT after 2-hour incubation at 37°C. FVIII activity is 2%. What is the diagnosis and treatment?

Answer: Acquired Hemophilia A (AHA)

Classic presentation: elderly patient, sudden-onset deep tissue/muscle bleed, NO prior bleeding history, isolated aPTT prolongation, incubated mixing study does NOT correct (time-dependent inhibitor = anti-FVIII IgG). Confirm with Bethesda assay (measures inhibitor titer). Acute bleeding management: Bypass agents (recombinant FVIIa 90 µg/kg q2-3h OR aPCC/FEIBA 50-100 U/kg q8-12h) — do NOT use standard FVIII concentrate (inhibitor renders it ineffective). Emicizumab (off-label) increasingly used. Inhibitor eradication: Prednisone 1 mg/kg/day ± rituximab (per EACH2 registry). Search for underlying cause: malignancy, SLE, postpartum, drugs.

Q6. A 55-year-old post-cardiac surgery patient received heparin for 8 days. His platelet count dropped from 230K to 55K (52% drop). No bleeding, but a new DVT is found in the left leg. 4T score is 6 (high probability). HIT ELISA is strongly positive. What is the immediate management?

Answer: Heparin-Induced Thrombocytopenia (HIT) with Thrombosis (HITT)

Immediate management: (1) STOP ALL HEPARIN immediately (IV, SC, flushes, LMWH, heparin-coated catheters); (2) Start non-heparin anticoagulant at FULL therapeutic dose: Argatroban (direct thrombin inhibitor — IV, hepatic clearance; preferred in renal failure) OR Fondaparinux (anti-Xa SC — no cross-reactivity with HIT antibody) OR Bivalirudin (cardiac surgery setting). (3) Do NOT give platelet transfusion (fuels thrombosis). (4) Do NOT start warfarin until platelets >150K (risk of venous gangrene). Functional confirmation: serotonin release assay (SRA — gold standard). After platelet recovery: transition to DOAC or warfarin. Warfarin requires argatroban overlap until INR ≥4 (argatroban elevates INR above true value).

Q7. A 25-year-old woman with recurrent miscarriages (3 at <10 weeks), a prior DVT at age 22 on OCP, and a recent stroke. Lab shows: lupus anticoagulant positive, anti-cardiolipin IgG >40 GPL, anti-β2-GPI IgG elevated. Results confirmed on repeat testing 14 weeks later. What syndrome does she have and what is the recommended long-term anticoagulation?

Answer: Antiphospholipid Syndrome (APS) — Triple Positive, High-Risk

Triple positive APS (LA + aCL + anti-β2GPI all positive) = highest thrombotic risk category. Long-term treatment: Warfarin (INR 2–3) — do NOT use DOACs in triple-positive APS. The TRAPS trial (NEJM 2018) demonstrated rivaroxaban was inferior to warfarin in high-risk APS, with significantly more arterial thrombotic events (stroke). For obstetric APS only (no thrombosis): low-dose aspirin + prophylactic LMWH during pregnancy. For future pregnancies with this patient: LDA + therapeutic LMWH throughout pregnancy + 6 weeks postpartum. Anticoagulation is lifelong given triple-positive status and prior arterial thrombosis.

10.3 Hematologic Malignancies — Questions

Q8. A 38-year-old presents with acute leukemia. PBS shows hypergranular blasts, some with Auer rods in bundles ("faggot cells"). Hb 7.8 g/dL, WBC 2.1K, platelets 18K. PT 22s, aPTT 48s, fibrinogen 0.9 g/L. What is the diagnosis and what treatment must be started immediately, even before genetic confirmation?

Answer: Acute Promyelocytic Leukemia (APL) with DIC

APL = AML M3 caused by t(15;17) PML-RARA fusion. Hypergranular promyelocytes with bundles of Auer rods ("faggot cells") = pathognomonic. DIC results from tissue factor and procoagulant enzymes in promyelocyte granules — can cause fatal intracranial hemorrhage within hours. Do NOT wait for cytogenetics/molecular confirmation. Start immediately: (1) ATRA 45 mg/m²/day PO (differentiates promyelocytes → resolves DIC); (2) Aggressive blood product support: FFP/cryoprecipitate (fibrinogen target >1.5 g/L), platelets >50K; (3) Add ATO 0.15 mg/kg IV once APL confirmed. Watch for: differentiation syndrome (fever, dyspnea, pulmonary infiltrates → dexamethasone 10 mg IV BID). Cure rate >95% with ATRA + ATO protocol.

Q9. A 70-year-old presents with back pain, normocytic anemia (Hb 9.4 g/dL), creatinine 2.8 mg/dL, calcium 11.8 mg/dL. X-ray shows multiple lytic lesions in the skull ("punched-out"). Serum protein electrophoresis shows an M-spike. BM biopsy shows 35% plasma cells. What are the diagnostic criteria met (CRAB), and what is the treatment approach?

Answer: Multiple Myeloma — CRAB criteria met (Calcium, Renal, Anemia, Bone)

All 4 CRAB criteria present: C (Ca 11.8), R (Cr 2.8), A (Hb 9.4), B (lytic bone lesions). This patient is transplant-ineligible (age 70). Management: (1) Induction with Dara-Rd (daratumumab + lenalidomide + dexamethasone) — MAIA trial OS benefit; or VRd (bortezomib + lenalidomide + dex); (2) Lenalidomide maintenance after induction; (3) Bone disease: Zoledronic acid 4 mg IV q4 weeks (or denosumab if CrCl <30); (4) Renal: hydration, avoid nephrotoxins — bortezomib-based regimen is renal-safe; (5) VTE prophylaxis (lenalidomide + dex = moderate VTE risk → aspirin or LMWH); (6) Antiviral prophylaxis (acyclovir) with bortezomib. Before starting daratumumab: alert blood bank for crossmatch interference (CD38 on RBCs → phenotype RBCs first).

Q10. A 45-year-old develops severe aplastic anemia: Hb 5.2, ANC 180/µL, platelets 8K. No HLA-matched sibling is available. BM biopsy shows <10% cellularity. PNH clone 3% by flow cytometry. What is the most appropriate treatment?

Answer: Immunosuppressive Therapy (IST) — Horse-ATG + Cyclosporine + Eltrombopag

Very severe aplastic anemia (ANC <200 = vSAA) without HLA-matched sibling donor → IST is the standard. Current standard (RACE Trial, NEJM 2022): Horse-ATG (h-ATG, ATGAM) + cyclosporine A + eltrombopag: 6-month CR 68% vs 41% with h-ATG + CsA alone. Eltrombopag added upfront stimulates residual stem cells via c-Mpl. Small PNH clone (3%) in this case does NOT require complement inhibitor at this size — monitor; treat aplasia with IST. If no response to h-ATG in 3–6 months → consider MUD (matched unrelated donor) SCT. Note: Do NOT use rabbit-ATG as first line for aplastic anemia (inferior to horse-ATG — Scheinberg NEJM 2011). G-CSF can be added to reduce infection risk during profound neutropenia.

10.4 Ultimate High-Yield Summary Table

🩸 High-Yield: Must-Know Hematology Board Topics

IDA vs Thalassemia trait: Both microcytic. IDA: RDW ↑, ferritin ↓↓, Mentzer index >13. Thal trait: RDW normal, HbA2 >3.5% (beta-thal), Mentzer <13.
Megaloblastic anemia: Hypersegmented neutrophils = B12/folate. MMA elevated = B12-specific. Never treat B12 def with folate alone (neurologic worsening).
TTP emergency: MAHA + thrombocytopenia → PEX immediately, no platelet transfusion. ADAMTS13 <10% confirms.
PNH: Hemolysis + thrombosis + pancytopenia. DAT negative. Flow cytometry: absent CD55/CD59. Start ravulizumab (preferred over eculizumab).
Warm AIHA: DAT positive (IgG ± C3). Treat: prednisone → rituximab → splenectomy. Transfuse only if life-threatening ("least incompatible").
Cold agglutinin: DAT positive (C3 only). IgM cold antibody. Keep warm. Sutimlimab (anti-C1s) FDA 2022. Steroids/splenectomy ineffective.
APL: Start ATRA immediately without waiting for confirmation. Faggot cells = pathognomonic. DIC management critical.
del(5q) MDS: Female, macrocytic anemia, elevated/normal platelets, hypolobulated megakaryocytes → lenalidomide.
APS: Triple positive → warfarin, NOT DOACs (TRAPS trial). Obstetric APS → LDA + LMWH in pregnancy.
HIT: Stop all heparin. Non-heparin anticoagulant (argatroban/fondaparinux). No platelets. No warfarin until plt >150K.
Acquired Hemophilia A: Elderly, deep bleed, isolated aPTT prolonged, NOT corrected by mixing study. Bypass agent (FVIIa/aPCC) + eradication (steroids ± rituximab).
Multiple Myeloma: CRAB criteria. Alert blood bank when starting daratumumab (CD38 crossmatch interference). Zoledronic acid for bone disease.
CML treatment goals: BCR-ABL1 ≤10% IS at 6 months (optimal). T315I = ponatinib or asciminib.
CAR-T therapy: Axicabtagene (DLBCL), ciltacel (myeloma — CARTITUDE-4), idecabtagene (myeloma). CRS and ICANS are key toxicities.

📚 Primary Sources for This Document

WHO Classification of Haematolymphoid Tumours, 5th Ed (2022)
ELN 2022 — AML, CML, MDS management guidelines
ASH 2021 — Anemia, ITP, VTE, AIHA guidelines
IMWG 2016/2020 — Myeloma criteria and response assessment
TIF Guidelines 2021 — Thalassemia management
WFH 2020 — Hemophilia management (3rd edition)
Dr. Parivat Thitiarayavich — Hemato Berlin 2026 (Thammasat University)
Dr. Pisa Phiphitaporn — Spot Diagnosis & Counseling in Hematology 2026 (Khon Kaen University)